Mutagenesis, Vol. 17, No. 3, 251-256,
May 2002
© 2002 UK Environmental Mutagen Society/Oxford University Press
Effect of ethanol treatment on metabolic activation and detoxification of esophagus carcinogenic N-nitrosamines in rat liver
Laboratory of Radiochemistry, Gifu Pharmaceutical University, 6-1, Mitahora-higashi 5-chome, Gifu 502-8585, Japan and 1 Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
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Abstract |
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In order to elucidate the mechanism underlying enhancement by ethanol of N-nitrosodiethylamine (DEN)- and N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in rats, hepatic levels of cytochrome P-450 (CYP) enzymes, mutagenic activation of several N-nitrosamines and three kinds of UDP-glucuronyltransferase (UDPGT) activities were assayed in F344 rats. Immunoblot analyses of microsomal CYP proteins revealed induction of CYP2E1 (~2-fold), but not CYP2B1/2, 1A1/2 or 3A2, by treatment with 10% ethanol in the drinking water for 2 weeks. In contrast, s.c. treatment with 0.5 mg/kg NMBA three times per week for 2 weeks produced no significant alterations in the levels of these CYP species. Ethanol treatment also elevated the mutagenic activities of N-nitrosodimethylamine (DMN), DEN and N-nitrosopyrrolidine (NPYR) in strain TA100 up to 2.1-, 1.6- and 2.3-fold above each control, respectively. However, this was not the cases for four N-nitrosamines, including NMBA, in strain TA100 and two heterocyclic amines and aflatoxin B1 in strain TA98. In addition, ethanol did not affect UDPGT activities towards 4-nitrophenol, bilirubin and testosterone. Hepatic CYP species responsible for mutagenic activation of selected N-nitrosodialkylamines were confirmed by use of specific CYP inducers and inhibitors with the liver from F344 and Wistar rats, indicating that DMN, DEN and NMBA are selectively activated by CYP2E1, predominantly by CYP2E1 with a slight contribution by CYP2B2 and selectively by CYP2B1/2, respectively. These results demonstrate that ethanol exerts an enhancing effect on mutagenic activation by CYP2E1 of DMN, DEN and NPYR, but does not affect that of NMBA and the other carcinogens by CYP2B1/2, 1A1/2 and 3A2 and UDPGT1A1, 1A6 and 2B1 activities. Consequently, this suggests that enhancement by ethanol of DEN-induced esophageal carcinogenesis in F344 rats can be attributed to an increase in hepatic activation during the initiation phase, but that of NMBA-induced tumorigenesis is not attributable to metabolic activation and inactivation via glucuronidation in liver.
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Introduction |
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Lifestyle factors such as chronic cigarette smoking and alcohol consumption are considered major risk factors in human cancer (Breslow and Enstrom, 1974
; Feldman and Hazan, 1975; Williams and Horm, 1977; Doll and Peto, 1981). Epidemiological studies have shown that alcohol consumption is mainly associated with cancers of the upper gastrointestinal tract (Tuyns, 1970, 1979; Wynder et al., 1977), liver (Tuyns, 1978; Lieber et al., 1979) and pancreas (Burch and Ansari, 1968). Seventy five percent of the esophageal cancers in the US are attributable to excessive alcohol drinking (Rothman, 1980). In fact, ethanol has been shown to enhance N-nitrosodiethylamine (DEN)-induced esophageal carcinogenesis in laboratory animals (Gibel, 1967; Griciute et al., 1982). Further, it has been demonstrated that ethanol shows an enhancing effect on DEN-induced esophageal tumorigenesis in F344 rats, when administered during the initiation phase (Aze et al., 1993). In contrast, Mufti et al. (1989) reported that the occurrence of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors is inhibited by simultaneous ethanol administration, but promoted when ethanol is administered post-initiation in Sprague–Dawley rats. Recently we have shown that NMBA-induced tumorigenesis is weakly enhanced by treatment with ethanol during the initiation (Kaneko et al., 2002) and promotion (Morimura et al., 2001) phases in F344 rats.
Ethanol treatment increases the alkylation of esophageal DNA by DEN, but not that of liver and kidney DNA, in female Wistar-derived rats (Swann et al., 1984). Further, isothiocyanate treatment markedly decreases the incidence and multiplicity of NMBA-induced esophageal tumors with inhibition of esophageal DNA methylation in F344 rats (Wilkinson et al., 1995), indicating the importance of metabolic activation of DEN and NMBA by cytochrome P-450 (CYP) in esophageal tumorigenesis. Since ethanol per se is not genotoxic and carcinogenic (Phillips and Jenkinson, 2001), its effects may be seen in terms of its modifying the effects of exogenous and endogenous carcinogens (Carlton et al., 1999).
Ethanol is known to be a hepatic CYP2E1 inducer in rodents (Miller and Yang, 1984; McCoy and Koop, 1988; Forkert et al., 1991). Furthermore, there are a few reports on induction of CYP2B1/2 protein by ethanol in rats (Johansson et al., 1988; Sinclair et al., 1991; Roberts et al., 1995), and CYP2E1 and CYP2B1/2 are specifically involved in metabolic activation of environmental N-nitrosamines to ultimate carcinogens. Rat CYP2E1 predominantly activates N-nitrosodimethylamine (DMN), DEN (Yang et al., 1987) and N-nitrosopyrrolidine (NPYR) (Gold and Brunk, 1988; Burke et al., 1994), all of which occur in cigarette smoke (International Agency for Research on Cancer, 1986), whereas CYP2B1 and 2B2 activate N-nitrosodialkylamines possessing relatively long alkyl chains (Mori et al., 1985; Kawanishi et al., 1992; Shu and Hollenberg, 1996). In addition, CYP1A2, CYP2A and CYP3A are reported to be responsible for metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in rats (Guo et al., 1992; Mori et al., 2001b), mice (Felicia et al., 2000) and humans (Kamataki et al., 1999). However, only limited data have been provided about the contribution of specific CYP species to metabolic activation of NMBA and to mutagenic activation of DMN and DEN.
Carcinogenic N-nitrosamines, including NMBA, are known to be substrates for UDP-glucuronyltransferases (UDPGTs) (Mori et al., 1984; Kokkinakis et al., 1987; Wiessler and Rossnagel, 1987). In the rat, hepatic UDPGT1A1, 1A6 and 2B1 are found as major enzymes which are inducible by clofibrate, 3-methylcholanthrene (MC) and phenobarbital (PB), respectively (Narayanan et al., 2000). UDPGT2B1 is suggested to be the probable enzyme responsible for glucuronidation of DEN and N-nitrosomethyl-n-pentylamine, while UDPGT1A6 is not (Wiench et al., 1992). However, no studies have been reported on the effect of ethanol on metabolic activity specific to UDPGT2B1 in rats. Meanwhile, reports of the action of ethanol on hepatic UDPGT1A6 and 1A1 activities show that they differ depending on sex (Hietanen et al., 1980; Reinke et al., 1986) and strain (Ideo et al., 1971; Hakim et al., 1972) in Sprague–Dawley and Wistar rats.
In order to elucidate the mechanism underlying enhancememt by ethanol of DEN- and NMBA-induced esophageal carcinogenesis, hepatic levels of microsomal CYP enzymes known to activate typical environmental carcinogens, mutagenic activation of several N-nitrosamines and three kinds of UDPGT activities were assayed in male F344 rats. We also report results on the CYP species responsible for metabolic activation of DEN and NMBA in F344 and Wistar rats.
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Materials and methods |
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Chemicals
NPYR, metyrapone and orphenadrine were obtained from Aldrich Chemical Co. (Milwaukee, WI) and aflatoxin B1 (AFB1) was from Makor Chemicals (Jerusalem, Israel). Hydrochlorides of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), DMN, DEN, PB, MC, 4-methylpyrazole, 4-nitrophenol, testosterone, bilirubin and UDP-glucuronic acid were purchased from Wako Pure Chemicals (Osaka, Japan) and NMBA was from Sakai Laboratory (Fukui, Japan). UDP-[14C(U)]glucuronic acid was purchased from American Radiolabeled Chemicals (St Louis, MO) and glucose 6-phosphate (G6P) dehydrogenase (G6PDH), G6P, NADP+, NADPH, NADH and ATP were from Oriental Yeast Co. (Tokyo, Japan). All other commercial products were of the purest grade available. N-nitrosobis(2-hydroxypropyl)amine (BHP) and N-nitroso-2,6-dimethylmorpholine (NDMM) were synthesized in our laboratory as described previously (Mori et al., 1985
) and NNK was kindly provided by Dr Akiyoshi Nishikawa (National Institute of Health Sciences, Tokyo, Japan).
Animal treatment and tissue preparation
Twenty male 6-week-old F344/DuCrj rats (Charles River Japan, Hino, Shiga, Japan) were divided into four groups consisting of five animals and treated with NMBA, ethanol or both. Rats in groups 1 and 2 received tap water ad libitum: group 1 rats were s.c. treated with 20% dimethyl sulfoxide (DMSO) three times per week for 2 weeks, serving as a control; group 2 rats received injections of 0.5 mg/kg NMBA dissolved in 20% DMSO. Group 3 and 4 rats were given 10% ethanol in the drinking water for 2 weeks and simultaneously treated with the vehicle and NMBA, respectively. All the animals were decapitated 24 h after the last dose of the vehicle or NMBA. Alternatively, male 6-week-old Wistar rats (Japan SLC, Hamamatsu, Japan) were i.p. injected once a day with PB (80 mg/kg) or MC (20 mg/kg) for 3 days and the animals starved for 24 h after the last dose. Livers were perfused in situ with ice-cold sterile 1.15% KCl and liver S9 and microsomal fractions were prepared using established procedures (Mori et al., 1985).
Western blotting
Goat anti-rat polyclonal antibodies for CYP1A1/2, 2B1/2, 2E1 and 3A2 (Daiichi Pure Chemicals Co., Tokyo, Japan) were used as primary antibodies. Gel electrophoresis and blot analysis were performed as described in detail previously (Koide et al., 1999) according to the established methods of Laemmli (1970) and Towbin et al. (1979), respectively. For quantitative analysis, immunoblots were digitally scanned using a Canon CanoScan 600 (Canon, Tokyo, Japan) and quantitated using Fuji Film MacBAS Software (Fuji Photo Film, Tokyo, Japan) on a Power Mac 8100 computer. Densitometry values were converted into pmol/mg protein using calibration curves, which were generated by loading various concentrations of CYP standards on gels together with samples.
Mutation assay
All tests were carried out by the Ames preincubation assay (Yahagi et al., 1977). The N-nitrosamines were dissolved in 100 µl of water and the other carcinogens in 50 µl of DMSO. The mutagenicity of Trp-P-2 and Glu-P-1 (0.03 µg/plate), AFB1 (1 µg), NNK (0.5 mg) and the other N-nitrosamines (1 or 10 mg) was checked in the presence of liver S9, according to the methods described by Smith et al. (1992), Ueno et al. (1978), Lee et al. (1996), Gold and Brunk (1988), Rumruen and Pool (1984) and Mori et al. (1985, 1993). The amount of liver S9 fraction was 10 µl/plate for the heterocyclic amines and AFB1, 50 µl for NNK and 150 µl for the other N-nitrosamines. Salmonella typhimurium TA100 and TA98 tester strains were employed for all the N-nitrosamines and the other carcinogens, respectively. The S9 mix contained the cofactors 4 mM NADPH, 4 mM NADH, 0.5 U G6PDH and 5 mM ATP, except for the N-nitrosamines, where 4 mM NADP+ and 5 mM G6P were used. One millimolar metyrapone (Ullrich et al., 1973), 0.1 mM 4-methylpyrazole (Newton et al., 1995) and 0.2 mM orphenadrine (Shu and Hollenberg, 1997) were preincubated with the carcinogen substrate and S9 mix in the experiments for CYP inhibition.
Assay of UDPGT activities
UDPGT activities towards 4-nitrophenol and bilirubin in liver microsomes were assayed according to the methods described by Isselbacher et al. (1962) and Heirwegh et al. (1972), respectively, and that towards testosterone was determined using UDP-[14C(U)]glucuronic acid as described by Matern et al. (1994).
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Results |
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To clarify the induction characteristics of ethanol and NMBA in mutagenic activation, NMBA and nine carcinogens known to be metabolically activated by specific CYP enzymes were assayed in strains TA100 and TA98 in the presence of liver S9 from F344 rats. As shown in Table I
, liver S9 from rats treated with ethanol for 2 weeks (groups 3 and 4) increased the mutagenic activities of DMN, DEN and NPYR up to 2.1-, 1.6- and 2.3-fold (P < 0.01), respectively, in the TA100 strain relative to that from group 1 rats. On the other hand, no significant alterations in mutagenicity were observed with NNK, NMBA, BHP and NDMM and there were no significant differences between groups 1 and 2 in the mutagenic activities of all these N-nitrosamines. Similarly, no treatments exerted a significant effect on the mutagenic activities of Glu-P-1, Trp-P-2 and AFB1 in the TA98 strain. Table II summarizes the effects of ethanol and NMBA on UDPGT activities towards 4-nitrophenol, bilirubin and testosterone in liver microsomes from the four groups of rats. Treatment with NMBA, ethanol or both did not produce significant alterations in UDPGT1A6, 1A1 and 2B1 activities.
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Figure 1
shows immunoblots and levels (pmol/mg protein) of microsomal CYP proteins in rats of the four groups. The hepatic level of CYP2E1 was 2.1-fold (P < 0.01) higher in group 3 and 4 rats than in group 1 rats, while that in group 2 rats was at the same level. CYP2B1 and CYP1A1 proteins were not constitutively expressed and were not induced in any group of rats and there were no significant differences in hepatic levels of CYP2B2, 1A2 and 3A2 among the four groups.
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In an attempt to obtain more information about the CYP species responsible for activation of three N-nitrosamines, including NMBA, typical CYP inducers and selective inhibitors were used in mutagenic activation assays. Figure 2
shows the effects of PB, MC and three inhibitors specific for CYP2B1, 2B2 and 2E1 on the mutagenic activity of NMBA in the presence of liver S9 from either F344 or Wistar rats. In the presence of liver S9 from control F344 rats (group 1), metyrapone caused 54% inhibition of the mutagenic activity, but orphenadrine and 4-methylpyrazole did not (Figure 2A). Treatment of Wistar rats with PB caused a 5.4-fold increase in activity, while MC treatment produced a 37% decrease (Figure 2B). As shown in Figure 2C, metyrapone and orphenadrine inhibited mutagenic activation in the presence of PB-treated rat liver S9 by 81 and 43%, respectively, while 4-methylpyrazole showed no significant inhibition. Figure 3 shows the effects of the CYP inhibitors on the mutagenicity of DMN and DEN in the presence of liver S9 from the ethanol-treated F344 rats in group 4. The mutagenic activities of DMN and DEN were inhibited 86 and 74%, respectively, by 4-methylpyrazole and the difference between inhibition of the two N-nitrosamines was statistically significant (P < 0.05). Metyrapone and orphenadrine caused no significant alteration in the activity of DMN, while that of DEN was decreased 37% by metyrapone, in spite of a lack of significant inhibition by orphenadrine.
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Discussion |
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Although 50 mg/kg N-nitrosobis(2-oxopropyl)amine is reported to slightly induce CYP2B species in hamster liver 6 h after treatment (Nishikawa et al., 1997
), NMBA treatment exerted no obvious effects on the levels of any CYP subfamilies determined in F344 rats. This is in agreement with previous findings in rats (Masuko et al., 1987) and mice (Mori et al., 2001a) treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. In contrast, ethanol showed a clear induction of microsomal CYP2E1 protein, but not CYP1A1/2, 2B1/2 and 3A2, consistent with the specificity of enhancement of the mutagenic potential of DMN, DEN and NPYR. However, this is not in agreement with previous findings that a liquid alcohol diet containing 50 g/l ethanol causes induction of CYP2B1/2 (Johansson et al., 1988; Roberts et al., 1995), 1A1 and 3A2 (Roberts et al., 1995) in Sprague–Dawley rats, in addition to CYP2E1, and that 200 mM ethanol induces CYP2B1/2 protein in cultured hepatocytes (Sinclair et al., 1991). The hepatic level of CYP2E1 protein in ethanol-treated rats is induced up to 9-fold higher than the level in untreated rats, while those of CYP1A1, 2B1/2 and 3A2 are increased 2- to 4-fold above corresponding controls (Johansson et al., 1988; Roberts et al., 1995). Therefore, it may be reasonable that ethanol did not increase the levels of CYP1A1, 2B1/2 and 3A2 under the experimental conditions used in the present study, since CYP2E1 was induced 2-fold by ethanol.
Induction of mutagenicity by ethanol treatment was slightly more efficient with DMN and NPYR than for DEN. A marked inhibition by 4-methylpyrazole, without inhibition by metyrapone and orphenadrine, of the enhanced activity of DMN indicates the involvement of CYP2E1, but not CYP2B1/2, in activation. On the other hand, a slight inhibition of the mutagenicity of DEN was found with metyrapone, but not with orphenadrine. Although 4-methylpyrazole also showed marked inhibition, this was slightly but significantly lower compared with the case of DMN, indicating the involvement of CYP2E1 and CYP2B2 in the activation of DEN. This is, to our knowledge, the first demonstration of differential contributions of CYP2E1 and CYP2B2 to mutagenic activation of DMN and DEN. These results are in line with the previous finding that CYP2E1 efficiently catalyzes dealkylation of DMN rather than DEN (Yoo et al., 1990). Together with lack of induction of the mutagenic activity of BHP by ethanol, these results clearly indicate different contributions of hepatic CYP2E1 and CYP2B1/2 to mutagenic activation of various N-nitrosodialkylamines, depending on the length of the alkyl chain (Mori et al., 1985; Kawanishi et al., 1992; Shu and Hollenberg, 1996). Further, induction of the mutagenicity of NPYR, but not NDMM, by ethanol treatment suggests similar differences in the contributions of CYP2E1 (Gold and Brunk, 1988; Burke et al., 1994) and CYP2B2 (Mori et al., 1985) to the activation of cyclic N-nitrosamines dependent on ring size.
PB increases the metabolic rate for benzaldehyde formation from NMBA in rat liver microsomes, whereas acetone and ethanol have no effect on benzaldehyde and formaldehyde formation (Yang et al., 1987). Similarly, PB enhances mutagenic activation of NMBA in strain TA1535 in the Ames test (Rumruen and Pool, 1984), while acetone and ethanol produce no significant changes in mutagenicity in the 6-thioguanine-resistant mutation assay (Yoo and Yang, 1985). These findings in rats are consistent with the present findings of mutagenicity in strain TA100 with liver S9 fractions from PB- and ethanol-treated rats, suggesting the involvement of CYP2B1/2, but not CYP2E1, in the activation of NMBA. The observations with selective CYP inhibitors used with PB-induced rat liver clearly demonstrate almost equal contributions of CYP2B1 and 2B2 to activation, without the involvement of CYP2E1. The involvement of CYP2B2 is also demonstrated in the case of liver S9 from control F344 rats in which constitutive CYP2B1 protein was not detected. Since hepatic CYP2B2 expression in rats is known to be decreased by >60% by MC (Imaoka et al., 1989; Mori et al. 2001b), the 37% decrease in mutagenic activity on MC treatment may be attributable to the decrease in constitutive CYP2B2 protein.
In the rat NNK is metabolically activated by CYP1A2, 2A1 and 3A2, but not by CYP1A1, 2B1 and 2E1 (Guo et al., 1992; Mori et al., 2001b). Glu-P-1 and Trp-P-2 are mutagenetically activated by CYP1A1/2 (Degawa et al., 1988; Koide et al., 1999; Mori et al., 2001b) and AFB1 by CYP2B1/2 and CYP3A2 (Buetler et al., 1996; Mori et al., 2001b). Accordingly, it is reasonable that no enhancement of the mutagenicity of these carcinogens by ethanol is observed, reflecting no changes in the hepatic levels of CYP1A1/2, 2B1/2 and 3A2. In addition, CYP2A1 is known to contribute more highly to NNK oxidation, i.e. formation of the keto alcohol, than CYP1A2 and 3A2 (Guo et al., 1992) and human CYP2A6 is clearly involved in mutagenic activation of NNK, while CYP2E1 is not (Kamataki et al., 1999). Accordingly, it may be suggested that ethanol cannot induce hepatic CYP2A1 protein.
No alterations in the three kinds of UDPGT activities were observed in ethanol- and/or NMBA-treated rats. We have confirmed induction of UDPGT1A6 and 2B1 activities in rat liver by typical inducers such as MC, PB and N-benzylimidazole under the experimental conditions used in the present study (Mori et al., 2001b), and the hepatic UDPGT1A1 activity obtained is comparable to previously reported results (Heirwegh et al., 1972; Magdalou et al., 1988). Conflicting results have been reported for the induction of UDPGT1A6 and 1A1 activities by ethanol: (i) ethanol enhances the MC-inducible activity in female Sprague–Dawley rats (Reinke et al., 1986) but not in male Wistar rats (Hietanen et al., 1980); (ii) the clofibrate-inducible activity is increased by ethanol in Wistar rats (Ideo et al., 1971) but not in Sprague–Dawley rats and humans (Hakim et al., 1972). Moreover, it is reported that hepatic mRNA levels for UDPGT1A1 and 2B1 in male Sprague–Dawley rats are enhanced by ethanol but that for UDPGT1A6 is not modified (Li et al., 2000). Since UDPGT1A6 activity towards 4-nitrophenol in ethanol-treated male F344 rats is in agreement with previous findings on the same substrate (Hietanen et al., 1980), as is the mRNA level (Li et al., 2000), it is concluded that ethanol has no effect on UDPGT1A6 activity in male rats. On the other hand, lack of induction of UDPGT1A1 activity towards bilirubin by ethanol is consistent with findings in Sprague–Dawley rats and humans, but does not agree with findings in Wistar rats, nor with the mRNA level in Sprague–Dawley rats. Lack of induction of UDPGT2B1 activity towards testosterone by ethanol is also not in accord with previous findings for the mRNA in Sprague–Dawley rats. The reasons for these discrepancies are not clear and remain to be clarified. Nevertheless, the present findings on UDPGT activities suggest that ethanol does not modify DEN- or NMBA-induced esophageal carcinogenesis via detoxification by these enzymes.
In conclusion, the present study has demonstrated that ethanol exerts an enhancing effect on mutagenic activation of DMN, DEN and NPYR by CYP2E1, but does not affect that of NMBA and other carcinogens by CYP2B1/2, 1A1 and/or 3A2 and UDPGT1A1, 1A6 and 2B1 activities. Consequently, the data indicate that enhancement of DEN-induced esophageal carcinogenesis in F344 rats by ethanol can be attributed to an increase in hepatic activation during the initiation phase, while enhancement of NMBA-induced tumorigenesis cannot be attributed to either metabolic activation or inactivation via glucuronidation in liver. This reflects a clearly different potency of ethanol in the enhancement of carcinogenesis initiated by DEN (Aze et al., 1993) and NMBA (Kaneko et al., 2002; Mutfi et al., 1993; Morimura et al., 2001). On the other hand, it has been shown that esophageal mucosal microsomes from untreated male Sprague–Dawley rats can form benzaldehyde and formaldehyde from NMBA at rates 1/5 and 1/60 of those in the liver, respectively (Labuc and Archer, 1982). Furthermore, ethanol is known to increase the total content of esophageal CYP in rats (Farinati et al., 1989), suggesting a mechanism for the enhancement of esophageal carcinogenesis induction by NMBA in the rat. However, the situation regarding CYP2B1/2 induction by ethanol in liver in relation to carcinogenicity enhancement remains to be demonstrated and further investigations on N-nitrosamine metabolism in the target organ and liver are now required.
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2 To whom correspondence should be addressed. Tel: +81 58 237 3931; Fax: +81 58 237 5979; Email: ymori{at}gifu-pu.ac.jp
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Aze,Y., Toyoda,K., Furukawa,F., Mitsumori,K. and Takahashi,M. (1993) Enhancing effect of ethanol on esophageal tumor development in rats by initiation of diethylnitrosamine. Carcinogenesis, 14, 37–40.
Breslow,N.E. and Enstrom,J.E. (1974) Geographic correlations between cancer mortality rates and alcohol-tobacco consumption in the United States. J. Natl Cancer Inst., 53, 631–639.
Buetler,T.M., Bammler,T.K., Hayes,J.D. and Eaton,D.L. (1996) Oltipraz-mediated changes in aflatoxin B1 biotransformation in rat liver: implications for human chemointervention. Cancer Res., 56, 2306–2313.
Burch,C.E. and Ansari,A. (1968) Chronic alcoholism and carcinoma of the pancreas; a correlative hypothesis. Arch. Intern. Med., 122, 273–275.
Burke,D.A., Wedd,D.J., Herriott,D., Bayliss,M.K., Spalding,D.J. and Wilcox,P. (1994) Evaluation of pyrazole and ethanol induced S9 fraction in bacterial mutagenicity testing. Mutagenesis, 9, 23–29.
Carlton,P.S., Gopalakrishnan,R., Gupta,A. and Stoner,G.D. (1999) Expression of cyclooxygenase-1 and cyclooxygenase-2 in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis. Clin. Cancer Res., 5 (suppl.), 3867s.
Degawa,M., Ueno,H., Miura,S., Ohta,A. and Namiki,M. (1988) A simple method for assessment of rat cytochrome P-448 isozymes responsible for the mutagenic activation of carcinogenic chemicals. Mutat. Res., 203, 333–338.[Web of Science][Medline]
Doll,R. and Peto,R. (1981) The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl Cancer Inst., 66, 1191–1308.
Farinati,F., Lieber,C.S. and Garro,A.J. (1989) Effects of chronic ethanol consumption on carcinogen activating and detoxifying systems in rat upper alimentary tract tissue. Alcohol Clin. Exp. Res., 13, 357–360.[Web of Science][Medline]
Feldman,J.G. and Hazan,M. (1975) A case-control investigation of alcohol, tobacco and diet in head and neck cancer. Prev. Med., 4, 444–463.[Web of Science][Medline]
Felicia,N.D., Rekha,G.K. and Murphy,S.E. (2000) Characterization of cytochrome P450 2A4 and 2A5-catalyzed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism. Arch. Biochem. Biophys., 384, 418–424.[Web of Science][Medline]
Forkert,P.G., Massey,T.E., Jones,A.B., Park,S.S., Gelboin,H.V. and Anderson,L.M. (1991) Distribution of cytochrome CYP2E1 in murine liver after ethanol and acetone administration. Carcinogenesis, 12, 2259–2268.
Gibel,W. (1967) Experimentelle Untersuchungen zur Synkarzinogenese beim Osophaguskarzinom. [Experimental studies on syncarcinogenesis in esophageal carcinoma.] Arch. Geschwulstforsch., 30, 181–189.[Medline]
Gold,B. and Brunk,G. (1988) The effect of pyrazole, phenobarbital, ethanol and 3-methylcholanthrene preteatment on the in vivo and in vitro genotoxicity of N-nitrosopyrrolidine. Carcinogenesis, 9, 1001–1005.
Griciute,L., Castegnaro,M. and Bereziat,J.C. (1982) Influence of ethyl alcohol on the carcinogenic activity of N-nitrosodi-n-propylamine. In Bartsch,H., Castegnaro,M., O'Neill,I.K., Okada,M. and Davis,W. (eds), N-Nitroso Compounds: Occurrence and Biological Effects. IARC Scientific Publications no. 41. IARC, Lyon, pp. 643–648.
Guo,Z., Smith,T.J., Thomas,P.E. and Yang,C.S. (1992) Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by inducible and constitutive cytochrome P450 enzymes in rats. Arch. Biochem. Biophys., 298, 279–286.[Web of Science][Medline]
Hakim,J., Feldmann,G., Troube,H., Boucherot,J. and Boivin,P. (1972) Comparative study of bilirubin and paranitrophenol glucuronyl transferase activities. II. Effect of chronic alcohol intoxication in man. Pathol. Biol. Paris, 20, 277–285.[Medline]
Heirwegh,K.P., Van de Vijver,M. and Fevery,J. (1972) Assay and properties of digitonin-activated bilirubin uridine diphosphate glucuronyltransferase from rat liver. Biochem. J., 129, 605–618.[Web of Science][Medline]
Hietanen,E., Koivusaari,U., Laitinen,M. and Norling,A. (1980) Hepatic drug metabolism during ethanol ingestion in riboflavin deficient rats. Toxicology, 16, 103–111.[Web of Science][Medline]
Ideo,G., De Franchis,R., Del Ninno,E., Cocucci,C. and Dioguardi,N. (1971) Increase of some rat liver microsomal enzymes as a consequence of prolonged alcohol intake: comparison with the effect of phenobarbitone. Enzyme, 12, 473–480.[Web of Science][Medline]
Imaoka,S., Terano,Y. and Funae,Y. (1989) Expression of four phenobarbital-inducible cytochrome P-450s in liver, kidney and lung of rats. J. Biochem., 105, 939–945.
International Agency for Research of Cancer (1986) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, no. 38, Tobacco Smoking. IARC, Lyon, pp. 83–126.
Isselbacher,K.J., Chrabas,M.F. and Quinn,R.C. (1962) The solubilization and partial purification of a glucuronyl transferase from rabbit liver microsomes. J. Biol. Chem., 237, 3033–3036.
Johansson,I., Ekstrom,G., Scholte,B., Puzycki,D., Jornvall,H. and Ingelman Sundberg,M. (1988) Ethanol-, fasting- and acetone-inducible cytochromes P-450 in rat liver: regulation and characteristics of enzymes belonging to the IIB and IIE gene subfamilies.Biochemistry, 27, 1925–1934.[Medline]
Kamataki,T., Nunoya,K., Sakai,Y., Kushida,H. and Fujita,K. (1999) Genetic polymorphism of CYP2A6 in relation to cancer. Mutat. Res., 428, 125–130.[Web of Science][Medline]
Kawanishi,T., Ohno,Y., Takanaka,A., Kawano,S., Yamazoe,Y., Kato,R. and Omori,Y. (1992) N-nitrosodialkylamine dealkylation in reconstituted systems containing cytochrome P-450 purified from phenobarbital- and beta-naphthoflavone-treated rats. Arch. Toxicol., 66, 137–142.[Web of Science][Medline]
Kaneko,M., Morimura,K., Nishikawa,T., Wanibuchi,H., Osugi,H., Koide,A., Mori,Y. and Fukushima,S. (2002) Weak enhancing effects of simultaneous ethanol administration on chemically induced rat esophageal tumorigenesis. Oncol. Rep., in press
Koide,A., Fuwa,K., Furukawa,F., Hirose,M., Nishikawa,A. and Mori,Y. (1999) Effect of cigarette smoke on the mutagenic activation of environmental carcinogens by rodent liver. Mutat. Res., 428, 165–176.[Web of Science][Medline]
Kokkinakis,D.M., Scarpelli,D.G., Subbarao,V. and Hollenberg,P.F. (1987) Species differences in the metabolism of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine. Carcinogenesis, 8, 295–303.
Labuc,G.E. and Archer,M.C. (1982) Esophageal and hepatic microsomal metabolism of N-nitrosomethylbenzylamine and N-nitrosodimethylamine in the rat. Cancer Res., 42, 3181–3186.
Laemmli,U.K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 680–685.[Medline]
Lee,C.K., Fulp,C.F., Bombick,B.R. and Doolittle,D.J. (1996) Inhibition of mutagenicity of N-nitrosamines by tobacco smoke and its constituents. Mutat. Res., 367, 83–92.[Web of Science][Medline]
Li,Y.Q., Prentice,D.A., Howard,M.L., Mashford,M.L., Wilson,J.S. and Desmond,P.V. (2000) Alcohol up-regulates UDP-glucuronosyltransferase mRNA expression in rat liver and in primary rat hepatocyte culture. Life Sci., 66, 575–584.[Web of Science][Medline]
Lieber,C.S., Seitz,H.K., Garro,A.J. and Worner,T.M. (1979) Alcohol-related dieseases and carcinogenesis. Cancer Res., 39, 2863–2886.
Magdalou,J., Totis,M., Boiteux Antoine,A.F., Fournel Gigleux,S., Siest,G., Schladt,L. and Oesch,F. (1988) Effect of 1-benzylimidazole on cytochromes P-450 induction and on the activities of epoxide hydrolases and UDP-glucuronosyltransferases in rat liver. Biochem. Pharmacol., 37, 3297–3304.[Web of Science][Medline]
Masuko,T., Sugahara,K., Nakajima,S. and Hashimoto,Y. (1987) Altered expression of immunohistochemically detected cytochrome P-450 component(s) in nitrosamine-induced rat urinary bladder lesion. Jpn. J. Cancer Res., 78, 840–845.[Web of Science][Medline]
Matern,H., Heinemann,H. and Matern,S. (1994) Radioassay of UDP-glucuronosyltransferase activities toward endogenous substrates using labeled UDP-glucuronic acid and organic solvent extraction procedure. Anal. Biochem., 219, 182–188.[Web of Science][Medline]
McCoy,G.D. and Koop,D.R. (1988) Biochemical and immunochemical evidence for the induction of an ethanol-inducible cytochrome P-450 isozyme in male syrian golden hamsters. Biochem. Pharmacol., 37, 1563–1568.[Web of Science][Medline]
Miller,K.W. and Yang,C.S. (1984) Studies on the mechanisms of induction of N-nitrosodimethylamine demethylase by fasting, acetone and ethanol. Arch. Biochem. Biophys., 229, 483–491.[Web of Science][Medline]
Mori,Y., Takahashi,H., Yamazaki,H., Toyoshi,K., Makino,T., Yokose,Y. and Konishi,Y. (1984) Distribution, metabolism and excretion of N-nitrosobis(2-hydroxypropyl)amine in Wistar rats. Carcinogenesis, 7, 375–379.
Mori,Y., Yamazaki,H., Toyoshi,K., Makino,T., Obara,T., Yokose,Y. and Konishi,Y. (1985) Mutagenic activation of carcinogenic N-nitrosopropylamines by rat liver: evidence for a cytochrome P-450 dependent reaction. Carcinogenesis, 6, 415–420.
Mori,Y., Iimura,K. and Hirano,K. (1993) N-benzylimidazole, a potent inducer of rat liver enzymes involved in mutagenic activation of various carcinogens. Mutat. Res., 302, 129–133.[Web of Science][Medline]
Mori,Y., Koide,A., Fuwa,K., Wanibuchi,H. and Fukushima,S. (2001a) Lack of changes in the levels of liver and kidney cytochrome P-450 isozymes in p53(+/–) knockout mice treated with N- butyl-N-(4-hydroxybutyl)nitrosamine. Mutagenesis, 16, 377–383.
Mori,Y., Koide,A., Fuwa,K. and Kobayashi,Y. (2001b) N-benzylimidazole for preparation of S9 fraction with multi-induction of metabolizing enzymes in short-term genotoxicity assays. Mutagenesis, 16, 479–486.
Morimura,K., Hori,T., Kaneko,M., Nishikawa,T., Nishikawa,A., Wanibuchi,H., Takada,N., Osugi,H. and Fukushima,S. (2001) Promotion of chemically induced rat esophageal tumorigenesis with post-initiation ethanol modification. Teratog. Carcinog. Mutagen., 21, 295–301.[Web of Science][Medline]
Mufti,S.I., Becker,G. and Sipes,I.G. (1989) Effect of chronic dietary ethanol consumption on the initiation and promotion of chemically induced esophageal carcinogenesis in experimental rats. Carcinogenesis, 10, 303–309.
Narayanan,R., LeDuc,B. and Williams,D.A. (2000) Determination of the kinetics of rat UDP-glucuronosyltransferases (UGTs) in liver and intestine using HPLC. J. Pharm. Biomed. Anal., 22, 527–540.[Web of Science][Medline]
Newton,D.J., Wang,R.W. and Lu,A.Y. (1995) Cytochrome P450 inhibitors. Evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab. Dispos., 23, 154–158.[Abstract]
Nishikawa,A., Lee,I.S., Uneyama,C., Furukawa,F., Kim,H.C., Kasahara,K., Huh,N. and Takahashi,M. (1997) Mechanistic insights into chemopreventive effects of phenethyl isothiocyanate in N-nitrosobis(2-oxopropyl)amine-treated hamsters. Jpn. J. Cancer Res., 88, 1137–1142.[Web of Science][Medline]
Phillips,B.J. and Jenkinson,P. (2001) Is ethanol genotoxic? A review of the published data. Mutagenesis, 16, 91–101.
Reinke,L.A., Moyer,M.J. and Notley,K.A. (1986) Diminished rates of glucuronidation and sulfation in perfused rat liver after chronic ethanol administration. Biochem. Pharmacol., 35, 439–447.[Web of Science][Medline]
Roberts,B.J., Shoaf,S.E. and Song,B.,J. (1995) Rapid changes in cytochrome P4502E1 (CYP2E1) activity and other P450 isozymes following ethanol withdrawal in rats. Biochem. Pharmacol., 49, 1665–1673.[Web of Science][Medline]
Rothman,K.J. (1980) The proportion of cancer attributable to alcohol consumption. Prev. Med., 9, 174–179.[Web of Science][Medline]
Rumruen,K. and Pool,B.L. (1984) Metabolic activation capabilities of S9 and hepatocytes from uninduced rats to convert carcinogenic N-nitrosamines to mutagens. Mutat. Res., 140, 147–153.[Web of Science][Medline]
Shu,L. and Hollenberg,P.F. (1996) Identification of the cytochrome P450 isozymes involved in the metabolism of N-nitrosodipropyl-, N-nitrosodibutyl- and N-nitroso-n-butyl-n-propylamine. Carcinogenesis, 17, 839–848.
Shu,L. and Hollenberg,P.F. (1997) Alkylation of cellular macromolecules and target specificity of carcinogenic nitrosodialkylamines: metabolic activation by cytochromes P450 2B1 and 2E1. Carcinogenesis, 18, 801–810.
Sinclair,J.F., McCaffrey,J., Sinclair,P.R., Bement,W.J., Lambrecht,L.K., Wood,S.G., Smith,E.L., Schenkman,J.B., Guzelian,P.S. and Park,S.S. (1991) Ethanol increases cytochromes P450IIE, IIB1/2 and IIIA in cultured rat hepatocytes. Arch. Biochem. Biophys., 284, 360–365.[Web of Science][Medline]
Smith,C., Payne,V., Doolittle,D.J., Debnath,A.K., Lawlor,T. and Hansch,C. (1992) Mutagenic activity of a series of synthetic and naturally occurring heterocyclic amines in Salmonella. Mutat. Res., 279, 61–73.[Web of Science][Medline]
Swann,P.F., Coe,A.M. and Mace,R. (1984) Ethanol and dimethylnitrosamine and diethylnitrosamine metabolism and disposition in the rat. Possible relevance to the influence of ethanol on human cancer incidence. Carcinogenesis, 5, 1337–1343.
Towbin,H., Staehelin,T. and Gordon,J. (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Biochemistry, 76, 4350–4354.
Tuyns,A.J. (1970) Cancer of the esophagus. Further evidence of the relation to drinking habits in France. Int. J. Cancer, 5, 152–156.[Web of Science][Medline]
Tuyns,A.J. (1978) Alcohol and cancer. Alcohol Health Res. World, 2, 20–31.[Medline]
Tuyns,A.G. (1979) Epidemiology of alcohol and cancer. Cancer Res., 39, 2840–2843.
Ueno,Y., Kubota,K., Ito,T. and Nakamura,Y. (1978) Mutagenicity of carcinogenic mycotoxins in Salmonella typhimurium. Cancer Res., 38, 536–542.
Ullrich,V., Frommer,U. and Weber,P. (1973) Characterization of cytochrome P-450 species in rat liver microsomes, I. Differences in the O-dealkylation of 7-ethoxycoumarin after pretreatment with phenobarbital and 3-methylcholanthrene. Hoppe-Seylers Z. Physiol. Chem., 354, 514–520.[Web of Science][Medline]
Wiench,K., Frei,E., Schroth,P. and Wiessler,M. (1992) 1-C-glucuronidation of N-nitrosodiethylamine and N-nitrosomethyl-n-pentylamine in vivo and in primary hepatocytes from rats pretreated with inducers. Carcinogenesis, 13, 867–872.
Wiessler,M. and Rossnagel,G. (1987) Alpha-glucuronides of N-nitrosomethylbenzylamine. In Bartsch,H., O'Neill,I. and Schulte-Hermann, R. (eds), The Relevance of N-Nitroso Compounds to Human Cancer, Exposure and Mechanism, IARC Scientific Publications no. 84. IARC, Lyon, pp. 170–172.
Wilkinson,J.T., Morse,M.A., Kresty,L.A. and Stoner,G.D. (1995) Effect of alkyl chain length on inhibition of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis and DNA methylation by isothiocyanates. Carcinogenesis, 16, 1011–1015.
Williams,R.R. and Horm,J.W. (1977) Association of cancer sites with tobacco and alcohol consumption and socioeconomic status of patients: interview study from the Third National Cancer Survey. J. Natl Cancer Inst., 58, 525–547.
Wynder,E.L., Mushinski,M.H. and Spivac,J.C. (1977) Tobacco and alcohol consumption in relation to the development of multiple primary cancers. Cancer, 40, 1872–1878.[Web of Science][Medline]
Yahagi,T., Nagao,M., Seino,Y., Matsusima,T., Sugimura,T. and Okada,M. (1977) Mutagenicities of N-nitrosamines on Salmonella. Mutat. Res., 48, 121–130.[Web of Science][Medline]
Yang,C.S., Patten,C., Lee,M.J., Li,M., Yoo,J.S., Pan,J. and Hong,J. (1987) Enzymatic mechanisms in the metabolic activation of N-nitrosodialkylamines. In Bartsch,H., O'Neill,I. and Schulte-Hermann R. (eds), The Relevance of N-Nitroso Compounds to Human Cancer, Exposure and Mechanism, IARC Scientific Publications no. 84. IARC, Lyon, pp. 104–108.
Yoo,J.S. and Yang,C.S. (1985) Enzyme specificity in the metabolic activation of N-nitrosodimethylamine to a mutagen for Chinese hamster V79 cells. Cancer Res., 45, 5569–5574.
Yoo,J.S., Ishizaki,H. and Yang,C.S. (1990) Roles of cytochrome P450IIE1 in the dealkylation and denitrosation of N-nitrosodimethylamine and N-nitrosodiethylamine in rat liver microsomes. Carcinogenesis, 11, 2239–2243.
Received on October 15, 2001; accepted on January 16, 2002.
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