Mutagenesis

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Mutagenesis, Vol. 14, No. 2, 217-220, March 1999
© 1999 UK Environmental Mutagen Society/Oxford University Press

Induced expression of CYP2A5 in inflamed trematode-infested mouse liver

R. Montero^1,3, G.J. Gentile², L. Frederick², J. McMannis², T. Murphy², G. Silva, H. Blankespoor² and J.M. Gentile²

¹ Instituto de Investigaciones Biomédicas, UNAM, México City, DF, México and ² Department of Biology, Hope College, Holland, MI 49423, USA

	Abstract

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Trematode infections have long been associated with specific types of cancer. We investigated the ability of the liver fluke Fasciola hepatica to alter host enzymes in a manner that might provide insight into the phenomenon of biologically associated cancers. Our data demonstrate an increased activity of the CYP2A5 isozyme in male mouse liver infected with F.hepatica. Induction of this enzyme was further assessed immunohistochemically. The infection affected CYP2A5 distribution in hepatic tissue. Inflammation and proliferation in liver tissue were observed at the same time that CYP2A5 activity increased. This enzyme is known to participate in the metabolism of several carcinogens which are commnon contaminants in environments of developing countries where parasitic infections may be prevalent.

	Introduction

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Trematode infections have long been associated with specific types of cancer (WHO/IARC, 1994). Proposed mechanisms include the production of NO₂ and HO by leukocytes in chronic inflammation (Ohshima and Bartsch, 1994; Rosin et al., 1994). Another possible mechanism suggests that the induction of enzymes that metabolize xenobiotics may be involved in the neoplastic process (Osuna et al., 1977; Everson et al., 1979; Gentile and DeRuiter, 1981). Infections by liver flukes and by hepatitis B viruses have been found to induce a specific CYP450 isozyme, CYP2A5 (Kirby et al., 1994a,b), which participates in the metabolism of carcinogens like aflatoxin B₁ (AFB₁) and several nitrosamines (Pelkonen et al., 1994).

In a previous study we demonstrated that hepatic microsomal enzymes (S9) prepared from livers of Fasciola hepatica-infected mice more readily transformed AFB₁ into its reactive metabolites than S9 from healthy animals (Gentile and DeRuiter, 1981). Kirby et al. (1994a) demonstrated a localized induction of CYP2A5 in the liver of hamsters infected with Opistorchis viverrini (another liver fluke) and in hepatitis B virus transgenic mice (Kirby et al., 1994b), which suggests that this enzyme is induced as part of a physiological reaction to infection. This reaction could make organisms more susceptible to damage by carcinogens such as AFB₁.

In order to investigate if F.hepatica can induce a similar reaction in mice, we infected animals with the parasite and analysed the induction of CYP2A5 by two methods: one based on coumarin metabolism, consisting of a biochemical determination of the 7-hydroxycoumarin metabolite in urine, and an immunohistochemical test to determine the induction of CYP2A5 in liver tissue. Phenobarbital (PB) served as a positive control for our experiments, since it has been shown that it induces CYP2A5 in mice (Pelkonen et al., 1994; Salonpää et al., 1994).

	Materials and methods

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Animals
Male ICRCDL/1 animals (6 weeks old) were obtained from Harlan Sprague Dawley Inc. (Indianapolis, IN).

Chemicals
Polyclonal chicken anti-mouse CYP2A5 was generously provided by Dr Risto Juvonen (University of Kuopio, Finland). Coumarin, 7-hydroxycoumarin, PB and 10% buffered formalin, along with all routine laboratory chemical reagents, were purchased from Sigma Chemical Co. (St Louis, MO). Secondary biotinylated rabbit anti-chicken IgG was obtained from Zymed (San Francisco, CA), while the ABC (avidin and biotinylated horseradish peroxidase macromolecular complex) kit, avidin–biotin blocking kit and diaminobenzidine substrate package were all obtained from Vector Laboratories (Burlingame, CA).

Treatment regimes for parasite exposure
Fasciola hepatica metacercariae were provided by Baldwin Enterprises (Monmouth, OR). In the initial set of experiments 12 animals were each exposed to five F.hepatica metacercaria via oral intubation. Infections were allowed to progress and each week they were tested for activity of CYP2A5 (also known as coumarin hydroxylase, COH) over 4 weeks. Animals in both the control and infected groups were placed into metabolism cages (1 animal/cage) for urine collection. Water was provided ad libitum and urine was collected for a 6 h period and then stored for subsequent analysis. In this set, an additional pool of six animals was exposed to a single i.p. injection of 80 mg/kg body wt PB diluted in 37.5% DMSO. Twenty four hours post-PB exposure the animals were injected with coumarin and urine collected as previously described. Following urine collection hepatic tissue was harvested from these animals for subsequent histological and immunohistochemical analysis.

In a second set of experiments infection with two metacercariae was allowed to progress for 5 and 10 days. At 5 days post-infection, six animals received coumarin as described and were killed 1 day after, by cervical dislocation. The remaining six animals in the infected group were treated and killed in the same way at 10 days post-exposure. In all cases hepatic tissue was obtained for histological and immunohistochemical analysis. A set of 10 uninfected animals of similar age served as controls.

CYP2A5 activity determination in urine (coumarin assay)
7-Hydroxycoumarin (7-OHC), the main metabolite of coumarin, was measured spectrofluorometrically in urine from coumarin-treated animals using methods originally described by Rautio et al. (1992) with slight modifications for its use in mice. After an overnight fast, animals were administered 50 mg/ml coumarin in a volume of 0.1 ml/10 g body wt i.p. and placed in metabolic cages where urine was collected over 6 h (1–3 ml were collected from each animal). Urine samples (25 µl) were mixed with 25 µl ß-glucuronidase (Sigma G-0751) in 2 mg/ml 1 N acetate buffer, pH 5.0, and incubated at 37°C for 30 min. After incubation, 200 µl H₂O and 1 ml chloroform were added to the tubes, shaken for 15 min at 37°C and centrifuged at 7500 r.p.m. for 2 min. An aliquot of 5 ml of the chloroform phase was added to 1.5 ml 1 M NaCl, 0.01 M NaOH, briefly vortexed and the alkaline phase immediately measured in a fluorometer at 360 nm excitation, 451 nm emission. A standard curve with known concentrations of 7-OHC and non-treated urine were simultaneously run. Differences were analyzed by Student's t-test.

Histological analysis of hepatic tissue
Liver tissue taken from animals treated according to the various regimes previously described was fixed in 10% buffered formalin for histological analysis. Fixed tissue was embedded in paraffin and serial histological sections were prepared. One of each series was stained with hematoxylin and eosin for subsequent microscopic analysis.

Blood smears and white cell differential count
Five blood smears were prepared at the time of death of each animal. They were allowed to dry for 1 day at room temperature and were then kept in refrigeration until stained. Giemsa was used for differential staining of white cells. Analysis consisted of the differential count of eosinophils, basophils, neutrophils, monocytes and lymphocytes in 100 leukocytes/slide, under a light microscope. Results are reported as the percentage of each cell type.

Immunohistochemical determination of CYP2A5
Serial tissue sections used for immunohistochemistry were deparaffinized using a xylene and alcohol series and endogenous peroxidase, biotin and non-specific antigenic sites were blocked by sequential incubation with 30% peroxide, 2% normal rabbit serum and with avidin–biotin blocking kit. Sections were incubated overnight with the primary antibody (polyclonal chicken anti-mouse CYP2A5) diluted 1:1500 in phosphate-buffered saline (PBS). This was followed by a 1 h incubation with a secondary biotinylated antibody (rabbit anti-chicken IgG) diluted 1:3000 in PBS. Final staining was performed with ABC reagent for 30 min followed by DAB–H₂O₂ staining for 3 min. Slides were analyzed by bright field microscopy.

	Results

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CYP2A5 activity induction
7-Hydroxycoumarin determination. Our data show an increased activity of CYP2A5 isozyme in F.hepatica-infected male mouse liver when compared with uninfected controls (Figure 1). Control mice showed a basal level activity of the enzyme, while animals infected showed increased activity as measured as a function of the concentration of the metabolite 7-hydroxycoumarin present in urine. The induced activity was already apparent at 5 days post-infection and remained high for 28 days (Figure 1). As expected, urine from PB-treated controls showed an increased concentration of the coumarin metabolite. A single treatment of 80 mg/kg PB produced a 2-fold increase in COH activity over controls (P = 0.05) and the induction pattern was similar to that seen in infected animals 5 days post-infection (Figure 1).

View larger version (41K): [in this window] [in a new window]   Fig. 1. Coumarin metabolite 7-hydroxycoumarin, measured in urine of mice infected with F.hepatica or treated with PB. Urine samples were taken at different stages of infection or the day after treating with 80 mg/kg PB. *P < 0.05; **P = 0.05; Student's t-test.

 
Immunohistochemistry and histological analysis. CYP2A5 was localized around bile ducts and central veins, similar to the localization of the enzyme in non-infected liver, but with increased concentration and distribution (Figure 2a and b) in infected animals. Induction by PB (Figure 2c) showed a similar pattern of distribution as found in infected animals.

View larger version (56K): [in this window] [in a new window]   Fig. 2. Identification of CYP2A5 in mouse liver: (a) healthy; (b) 15 days after infection; (c) 1 day after PB treatment. No counterstaining was done and tissue sections were photographed in phase contrast. The immunohistochemical stain was revealed only in cells where anti-CYP2A5 reacted with its antigen and the cells appear dark and nuclei are white. Even though there is a base level concentration of CYP2A5 in liver, it is increased in the infected tissue and in the PB-treated liver, as evidenced by the intense antigen–antibody reaction and its wider distribution (DAB–peroxidase stain, 78.75x, phase contrast).

 
Inflammation and induced hepatocyte proliferation. Histological analysis revealed that the passage of the parasite through the liver produces injury promoting an inflammatory reaction. Damage was observed as isolated foci distributed throughout the organ. Eosinophils, lymphocytes and Kupfer cells were the main cell types observed in damaged areas.

The increase in eosinophil number was confirmed in peripheral blood smears from the infected animals. A 15% eosinophil proportion was found as compared with 2.1% normally found in mice.

When inflammation was severe, covering extended areas of tissue, CYP2A5 induction was observed in intact tissue adjacent to these areas of inflammation (Figure 3a and b). In contrast to these observations, PB produced different alterations in hepatocytes. There were no changes in leukocyte proportions in blood and swollen hepatocytes could be observed in the same areas where proliferation was induced.

View larger version (126K): [in this window] [in a new window]   Fig. 3. Serial sections of an inflamed region in infected liver. (a) Leukocytes (small dark nuclei, indicated by arrows) have intruded into the hepatic parenchyma from the blood vessel seen at the right (hematoxylin/eosin stain, bright field microscopy, 78.75x). (b) When the immunohistochemical staining procedure was done, the hepatocytes lining the inflammed area were stained as well as those around central veins (some are encircled); leukocytes in the parenchima did not stain (78.75x, phase contrast, no counterstain was used).

 
We observed proliferating cells as mitotic figures and in areas where cells presented enlarged nuclei with smooth chromatin, presumably in S phase, both in infected and in PB-treated liver.

Irrespective of the treatment, proliferation was induced by infection and by PB treatment, which simultaneously induced CYP2A5 in mouse liver. Both inductions were evident at early stages of infection or the day after a single administration of PB.

	Discussion

Top Abstract Introduction Materials and methods Results Discussion References

 
CYP2A5 induction
The induction of CYP2A5 in F.hepatica-infected animals supports the hypothesis that parasites can alter the activity of key hepatic enzymes. These data support previous studies which demonstrated that the S9 microsomal fraction isolated from liver of infected animals more efficiently activated AFB₁ into DNA-reactive forms (Gentile and DeRuiter, 1981). Kirby et al. (1994a) found a similar induction of CYP2A5 in hamsters infected with O.viverrini and demonstrated an increased frequency of AFB₁–DNA adducts in the same areas of the tissue where the enzyme was induced.

According to Salonpää et al. (1995) and Camus-Randon et al. (1996), mouse hepatic CYP2A5 expression is often increased under conditions in which other P450 isoforms are repressed, particularly after the administration of heavy metals and other porphyrinogenic agents known to affect cellular heme balance, causing an induction of CYP2A5 activity reaching levels of 4- to 26-fold over control values. Tekwani et al. (1988) found that total CYP450 content is reduced by some parasite infections and Monshouwer et al. (1996) showed that products of inflammation can suppress CYP450 enzyme activity by the production of cytokines. Tinel et al. (1995) demonstrated that the IL-2 receptor in rat hepatocytes played a role in the down-regulation of CYP450 expression. Our results showed an induced CYP2A5 activity in infected animals with an inflammatory reaction. These data complement and extend those of Kirby et al. (1994a) in studies with O.viverrini.

From our data we cannot conclude that CYP2A5 induction is associated with heme balance (as suggested by Salonpää et al., 1995), but evidence shows that CYP2A5 expression occurs whenever there is liver injury (Camus-Randon et al., 1996). This is in agreement with our previous study (Vandewaa et al., 1982) in which we found increased AFB₁ metabolism in S9 from partially hepatectomized mice. Lastly, recent data produced in our laboratory using the polyaromatic hydrocarbon benzo[a]pyrene and the aromatic amine 2-aminofluorene show that, unlike aflatoxin, these promutagens are not activated preferentially by S9 from parasite-infested liver. This further supports our evidence for specific induction of CYP2A5 in the traumatized liver tissue rather than an overall increase in CYP450 activity (unpublished observations). The common denominator identifiable in all of these studies is injury which resulted in inflammation, cell death and proliferation.

Hepatocyte proliferation
Proliferation of hepatocytes can be a consequence of cell death and inflammation in the infected liver (Robbins and Kumar, 1987). Proliferation is important since it can provide the opportunity for xenobiotics to interact with DNA and to fix the mutations that could play a role in the initiation or the progression of the neoplastic process (Craddock, 1973; Cayama et al., 1978; Cohen and Ellwein, 1990). Xenobiotics often induce proliferation directly or indirectly (Preston-Martin et al., 1990). In this case, PB is known to stimulate transient liver growth in rodents (Leibold and Schwarz, 1996) and is also a known tumor promoter (Takagi et al., 1993; Armato et al., 1992).

The CYP2A subfamily is one of the important CYP450 families in the metabolism of xenobiotics. CYP2A5 (and CYP2A6 in humans) is known to participate in the metabolism of carcinogens such as AFB₁, nitrosamines and butadiene (Pelkonen et al., 1994; Camus et al., 1993; Duescher and Elfarra, 1994). It is also induced by cocaine, before cocaine-associated liver toxicity is induced (Pellinen et al., 1994). Our results show that F.hepatica can cause liver injury, triggering a physiological response involving the activation of metabolism enzymes and proliferation of the affected tissue, which could render the host more susceptible to the action of selected environmental agents.

Metabolic enzyme polymorphisms have been recognized as important when assessing individual variability in susceptibility to genetic damage (Bochkov and Titenko, 1991). It has also been recognized that the genetic make-up can be modified by nutritional status, rendering a different kind of susceptibility, due to protein levels and enzyme activity (Dunki Jacobs et al., 1989a,b; Turturro et al., 1996). Similar events could occur in parasitized individuals, where specific induction and/or inhibition of enzymes may alter their susceptibility to specific xenobiotics, as suggested by our results.

In Asian, African and Latin-American countries nitrosamines and AFB₁ are often present in food and infectious diseases are frequent (WHO/IARC, 1994; Sistema Nacional de Vigilancia Epidemiológica, 1996). The way these conditions translate into a deterioration in health is of anthropological and medical importance. Studies must be undertaken to assess if effects similar to those demonstrated here occur in humans. Such studies will provide valuable information relative to public health risks for a large number of people world wide and will enhance the overall understanding of neoplastic risk associated with chronic inflammation.

	Acknowledgments

 
We thank Drs Miriam Poirier and Ofelia Olivero for valuable orientation about the immunohistochemical work, Ms Lisa Brenner for part of the histological work and the Veterinarian Gerardo Arrellín for tutoring us with the pathological analysis. We are also grateful to Mr José Avilés and to the Microphotography Laboratory of the Faculty of Sciences, UNAM, for the photographic work. This research was supported by the Howard Hughes Medical Institute and Dr Montero's stay at Hope College was supported by a fellowship from CONACYT, México.

	Notes

 
³ To whom correspondence should be addressed. Tel: +52 5 622 3845; Fax: +52 5 550 0048; Email: dorinda{at}servidor.unam.mx

	References

Top Abstract Introduction Materials and methods Results Discussion References

 

Armato,U., Testolin,L., Menegazzi,M., Menapace,L., Ribecco,M., Carcereri de Prati,A., Miwa,M. and Suzuki,H. (1992) The exposure of carcinogen-initiated primary neonatal rat hepatocytes to tumor promoters modulates both the transcripts and the enzymatic activity of nuclear poly(ADP-ribose) polymerase. Biochem. Biophys. Res. Commun., 182, 1066–1074.[Web of Science][Medline]

Bochkov,N.P. and Titenko,N.V. (1991) Genetic predisposition to environmental toxic agents: detection by distribution of ecogenetic markers. In Grandjean,P. (ed.), Ecogenetics. Genetic Predisposition to the Toxic Effects of Chemicals. WHO–Chapman and Hall, London, UK.

Camus,A., Geneste,O., Honkakoski,P., Bereziat,J., Henderson,C.J., Wolf,C.R., Bartsch,H. and Lang,M.A. (1993) High variability of nitrosamine metabolism among individuals: role of cytochromes P450 2A6 and 2E1 in the dealkylation of N-nitrosodimethylamine and N-nitrosodiethylamine in mice and humans. Mol. Carcinog., 7, 268–275.[Web of Science][Medline]

Camus-Randon,A.M., Raffalli,F., Béréziat,J.C., McGregor,D., Konstandi,M. and Lang,M. (1996) Liver injury and expression of cytochromes P450: evidence that regulation of CYP2A5 is different from that of other major xenobiotic metabolizing CYP enzymes. Toxicol. Appl. Pharmacol., 138, 140–148.[Web of Science][Medline]

Cayama,E., Tsuda,H., Sarma,D.S.R. and Farber,E. (1978) Inititation of chemical carcinogenesis requires cell proliferation. Nature, 275, 60–62.[Medline]

Cohen,S.M. and Ellwein,L.B. (1990) Cell proliferation in carcinogenesis. Science, 249, 1007–1011.[Abstract/Free Full Text]

Craddock,V.M. (1973) Induction of liver tumours in rats by a single treatment with nitroso compounds given after partial hepatectomy. Nature, 245, 386–388.[Medline]

Duescher,R.J. and Elfarra,A.A. (1994) Human liver microsomes are efficient catalysts of 1,3-butadiene oxidation: evidence for major roles by cytochromes P450 2A6 and 2E1. Arch. Biochem. Biophys, 311, 342–349.[Web of Science][Medline]

Dunki Jacobs,P.B., Ruevekamp,M., Hart,G.A. and de Graaf,P.W. (1989a) Dietary influences on cell proliferation in bone marrow. Eur. J. Cancer Clin. Oncol., 25, 953–957.[Web of Science][Medline]

Dunki Jacobs,P.B., Ruevekamp,M., Varossiau,F.J., Hart,G.A. and de Graaf,P.W. (1989b) Alterations in serum levels, anti-tumor activity and toxicity of methotrexate in rats after a short period of nutritional depletion. Eur. J. Cancer Clin. Oncol., 25, 415–422.[Web of Science][Medline]

Everson,R.B., Gad-el-Mawia,N.M., Chevien,E.M., Thorgeirsson,S.S., Alexander,L.A. and Ziegler,J.L. (1979) A preliminary search for chemical mutagens associated with carcinoma of the bilharzial bladder. Proc. Environ. Mutagen. Soc., 10, 106.

Gentile,J.M. and De Ruiter,E. (1981) Promutagen activation in parasite-infected organisms: preliminary observations with Fasciola hepatica-infected mice and aflatoxin B₁. Toxicol. Lett., 8, 273–282.[Web of Science][Medline]

Kirby,G.M., Pelkonen,P., Vatanasapt,V., Camus,A.M., Wild,C.P. and Lang,M. (1994a) Association of liver fluke (Opisthorchis viverrini) infestation with increased expression of cytochrome P450 and carcinogen metabolism in male hamster liver. Mol. Carcinog., 11, 81–89.[Web of Science][Medline]

Kirby,G.M., Chemin,Y., Montesano,R., Chisari,F.V., Lang,M.A. and Wild,C.P. (1994b) Induction of specific cytochrome P450s involved in aflatoxin B₁ metabolism in hepatitis B virus transgenic mice. Mol. Carcinog., 11, 74–80.[Web of Science][Medline]

Leibold,E. and Schwarz,L.R. (1996) Phenobarbital transiently stimulates uptake of 2-aminoisobutyric acid in hepatocytes. Arch. Toxicol., 70, 368–372.[Web of Science][Medline]

Monshouwer,M., Witkamp,R.F., Nujmeijer,S.M., Van Amsterdam,J.G. and Van Miert,A.S. (1996) Suppression of cytochrome P450- and UDP glucuronosyl transferase-dependent ezyme activities by proinflammatory cytokines and possible role of nitric oxide in primary cultures of pig hepatocytes. Toxicol. Appl. Pharmacol., 137, 237–244.[Web of Science][Medline]

Ohshima,H. and Bartsch,H. (1994) Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat. Res., 305, 253–264.[Web of Science][Medline]

Osuna,O., Edds,G.T. and Blankespoor,H. (1977) Toxic effects of aflatoxin B₁ in male holstein calves with prior infection by flukes (Fasciola hepatica). Am. J. Vet. Res., 38, 341–349.[Web of Science][Medline]

Pelkonen,P., Kirby,G.M., Wild,C.P., Bartsch,H. and Lang,M.A. (1994) Metabolism of nitrosamines and aflatoxin B₁ by hamster liver CYP2A enzymes. Chem. Biol. Interact., 93, 41–50.[Web of Science][Medline]

Pellinen,P., Stenbäck,F., Raunio,H., Pelkonen,O. and Pasanen,M. (1994) Modification of hepatic cytochrome P450 profile by cocaine-induced hepatotoxicity in DBA/2 mouse. Eur. J. Pharmacol. Environ. Toxicol. Pharmacol. Sect., 292, 57–65.[Web of Science][Medline]

Preston-Martin,S., Pike,M.C., Ross,R.K., Jones,P.A. and Henderson,B.E. (1990) Increased cell division as a cause of human cancer. Cancer Res., 50, 7415–7421.[Abstract/Free Full Text]

Rautio,A., Kraul,H., Kojo,A., Salmela,E. and Pelkonen,O. (1992) Interindividual variability of coumarin 7-hydroxylation in healthy volunteers. Pharmacogenetics, 2, 227–233.[Web of Science][Medline]

Robbins,S. and Kumar,V. (1987) Inflammation and Repair. In Robbins,S. and Kumar,V. (eds), Basic Pathology, 4th Edn. WB Saunders Co., Philadelphia, PA, pp. 28–62.

Rosin,M.P., El Din Zaki,S.S., Ward,A.J. and Anwar,W.A. (1994) Involvement of inflammatory reactions and elevated cell proliferation in the development of bladder cancer in schistosomiasis patients. Mutat. Res., 305, 283–292.[Web of Science][Medline]

Salonpää,P., Pelkonen,O., Kojo,A., Pasanen,M., Negishi,M. and Raunio,H. (1994) Cytochrome P4502A5 expression and inducibility by phenobarbital is modulated by cAMP in mouse primary hepatocytes. Biochem. Biophys. Res. Commun., 205, 631–637.[Web of Science][Medline]

Salonpää,P., Krause,K., Pelkonen,O. and Raunio,H. (1995) Up-regulation of CYP2A5 expression by prophyrinogenic agents in mouse liver. Naunyn-Schmiedeberg's Arch. Pharmacol., 351, 446–452.[Web of Science][Medline]

Sistema Nacional de Vigilancia Epidemiológica (1996) Epidemiología, 13, 3–15.

Takagi,H., Sharp,R., Takayama,H., Anver,M.R., Ward,J.M. and Merlino,G. (1993) Collaboration between growth factors and diverse chemical carcinogens in hepatocarcinogenesis of transforming growth factor alpha transgenic mice. Cancer Res., 53, 4329–4336.[Abstract/Free Full Text]

Tekwani,B.L., Shukla,O.P. and Ghatak,S. (1988) Altered drug metabolism in parasitic diseases. Parasitol. Today, 4, 4–10.[Web of Science][Medline]

Tinel,M. et al. (1995) The interleukin-2 receptor down-regulates the expression of cytochrome P450 in cultured rat hepatocytes. Gastroenterology, 109, 1589–1599.[Web of Science][Medline]

Turturro,A., Duffy,P., Hart,R. and Allaben,W.T. (1996) Rationale for the use of dietary control in toxicity studies—B6C3F1 mouse. Toxicol. Pathol., 24, 769–775.[Abstract/Free Full Text]

Vandewaa,E.A., Barney,C.C. and Gentile,J. (1982) Promutagen activation in partially hepatectomized mice. Toxicol. Lett., 14, 253–260.[Web of Science][Medline]

WHO/IARC (1994) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 61, Schistosomes, Liver Flukes and Helicobacter pylori. IARC, Lyon, France.

Received on July 13, 1998; accepted on November 12, 1998.

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