Mutagenesis, Vol. 18, No. 1, 95-100,
January 2003
© 2003 UK Environmental Mutagen Society/Oxford University Press
Modulation of rat liver citochrome P450 by protein restriction assessed by biochemical and bacterial mutagenicity methods
1 CIBIOMED, ICBP ‘Victoria de Girón’, Ciudad Habana, Cuba, 2 Torre de Investigación ‘Joaquín Cravioto’, Instituto Nacional de Pediatría, Insurgentes Sur, 3700-C, 04530 México, D.F., México and 3 Instituto de Investigaciones Biomédicas, UNAM, Apartado Postal 70228, 04510 México, D.F., México
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Abstract |
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Protein restriction (PR) significantly inhibits spontaneous and chemical carcinogenesis. Several factors seem to be involved in this effect, including a decrease in body weight, cellular proliferation and DNA damage and an increase in antioxidant defenses. The current study was designed to determine modifications in some hepatic cytochromes P450 (CYPs) due to a hypoproteic diet and to investigate its implications on chemical mutagenesis. Western blot analysis showed decreases of 73, 40 and 74% in CYP1A, CYP2B and CYP2E1 protein concentrations in hepatic microsomes from animals fed a protein-restricted (6% protein) diet for 6 weeks in comparison with microsomes from rats fed a 24% protein diet during the same period. In the same way, low protein fed animals showed a 3.5-fold decrease in hepatic CYP1A1-associated ethoxyresorufin O-deethylase activity, a 6-fold decrease in CYP1A2-associated methoxyresorufin O-demethylase activity, a 1.7-fold decrease in CYP2B1-associated penthoxyresorufin O-dealkylase activity, a 9-fold decrease in CYP2B2-associated benzyloxyresorufin O-dealkylase and, finally, a 3.4-fold decrease in CYP2E1-associated 4-nitrophenol hydroxylase activity. As a result of decreased CYP hepatic protein concentrations and enzymatic activities, liver S9 from rats fed a hypoproteic diet was less efficient in activating promutagens than S9 prepared from rats fed a 24% protein diet in the Ames test. Mutagenic potency obtained with protein-restricted S9 was reduced 25-fold for 2-aminoanthracene, 1.5-fold for N-nitrosodipropylamine, 12.5-fold for N-nitrosodibutylamine, 2-fold for cyclophosphamide and N-nitrosopyrrolidine and 71-fold for N-nitrosodimethylamine. However, the mutagenic potency of benzo[a]pyrene was the same (4 revertants/µg) with S9 derived from rats fed either a 6 or 24% protein diet.
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Introduction |
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Dietary restriction inhibits chemically induced carcinogenesis and the incidence of spontaneous tumors in the mammary gland, lung and liver by 50% or more (Tannenbaum, 1942
). Potential mechanisms for the inhibition of cancer by dietary restriction include decreases in body weight, oxidative damage, cellular proliferation and DNA damage (Hart and Turturro, 1997). Protein restriction has also been shown to decrease tumorigenesis (Hawrylewiez et al., 1982). The precise mechanisms by which protein restriction evokes its effects on cancer and longevity have not been determined, nevertheless, there is evidence for an increase in antioxidant enzyme defenses (Youngman, 1990), immune surveillance (Bell et al., 1990), increased physical activity (Krieger et al., 1988), reduced body size, decreased cell division rates in many tissues (Youngman, 1993) and metabolic rate reduction (Horio et al., 1991) induced by a protein restricted diet. Protein restriction appears to have many effects, interacting at various levels of organization and with many important toxicity-inducing factors (Hart et al., 1995).
Metabolism of xenobiotics plays an important role in chemical carcinogenesis (Hursting and Kari, 1999). The carcinogenic potency of many of these chemicals is dependent upon their metabolic biotransformation to electrophilic active intermediates (Badawi et al., 1996). Included in the enzymes responsible for this effect are the cytochromes P450 (CYPs) (Parke et al., 1991; Hursting and Kari, 1999). CYPs are a superfamily of enzymes that participate in the redox activation of xenobiotics and endogenous compounds. CYP activity may also result in the generation of potentially toxic hydroxyl and superoxide radicals (Guengerich and Shimada, 1991). Similarities in CYP amino acid sequence have been used for their classification into different families and subfamilies (Nelson et al., 1993), some of which, namely CYP1A, CYP2E and CYP2B, have been shown to play a major role in the activation of chemical carcinogens and detoxification of foreign compounds (Lewis and Sheridan, 2001). The expression of CYPs, together with other enzymes, could be considered as biomarkers of human cancer susceptibility (Badawi et al., 1996).
The reasons mentioned above justify studies of the modulation of CYPs expression as a good strategy for the development of cancer prevention. Although there is evidence showing inhibition of some CYP enzymatic activities in hepatic microsomes from rodents fed a low protein diet (Cho et al., 1999; Zhang et al., 1999), the relationship between the observed reduction in specific CYP-related activities and hepatic activation of model mutagenic compounds have not been explored in detail.
Because of the current interest in understanding the mechanisms involved in the protective effect of protein restriction, the aim of this work was to study the possible modulating capacity of a hypoproteic diet on the expression of several CYPs involved in chemical mutagenesis/carcinogenesis. We also evaluated whether this modulating capacity would have repercussions on chemical mutagenesis, since it is considered to be a critical event in the carcinogenic process.
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Materials and methods |
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Chemicals
ß-NADP, glucose-6-phophate (G6P), N-nitrosodipropylamine (NDPA), N-nitrosopyrrolidine (NPYR), N-nitrosodimethylamine (NDMA), N-nitrosodibutylamine (NDBA), benzo[a]pyrene (B[a]P), 2-aminoanthracene (2-AA), cyclophosphamide (CP), anti-mouse immunoglobulin IgG–peroxidase conjugate, methoxyresorufin, 7-pentoxyresorufin, 7-benzyloxyresorufin, resorufin ethoxyresorufin, albendazole, ß-naphthoflavone (NF), 4-nitrophenol and 4-nitrocatechol were purchased from Sigma Chemical Co. (St Louis, MO). Goat polyclonal anti-rat CYP1A1/2, CYP2B1/2, CYP2E1 antisera, along with microsome standards for each CYP, were manufactured by Daiichi Pure Chemicals Co. and purchased from Gentest Corp. Chemicals for electrophoresis and nitrocellulose membranes were purchased from Bio-Rad (Richmond, CA).
Animal treatment
Male Wistar rats were weaned at 21 days of age and divided ramdomly into one of two groups and fed one of the following isocaloric diets (AbeneMR, México, D.F., México) (Table I): five rats were assigned to the control group and given a diet with 24% casein as the sole source of protein; 12 rats were assigned to the restricted diet group with 6% casein as the sole source of protein. Animals were housed in polypropylene cages and subjected to a 12 h light–dark cycle in an animal care facility and consumed water and food ad libitum until killed.
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Preparation of S9 and microsomal fraction
Liver S9 fractions were prepared according to the procedure described by Maron and Ames (1983)
. After the last day of treatment, animals were killed by cervical dislocation and livers were freshly excised and washed in 150 mM KCl solution. Samples were minced into small pieces and homogenized in the same solution (3 ml/g liver). The homogenates were centrifuged at 9000 g for 10 min and the supernatant (S9) was conserved at –80°C. A portion of this supernatant fraction was centrifuged at 105 000 g for 1 h; the microsomal pellets were resuspended in phosphate buffer solution (67.5 mM K2HPO4 and 32.5 mM KH2PO4, pH 7.4) and centrifuged again. Finally, the microsomes were homogenized in the same phosphate buffer solution containing 1 mM dithiothreitol, 1 mM EDTA and 20% glycerol. All procedures were conducted aseptically at 4°C. Protein content was determined by the Bradford (1976) method.
Gel electrophoresis and immunoblot analysis
Five micrograms of protein was separated on a 10% SDS–polyacrylamide gel (Laemmli, 1970) and were subsequently transferred to a 0.45 µm nitrocellulose sheet (Towbin et al., 1979). The nitrocellulose membrane was blocked overnight with 5% non-fat dry milk dissolved in saline (20 mM NaCl, 2.5 mM Tris–HCl, pH 7.4, and 0.05 Tween 20). The blots were washed for 10 min with phosphate-buffered saline containing 0.3% Tween 20 and probed for 1 h with an anti-rat primary antibody (1:400) that recognizes CYP1A1/2, CYP2B1/2 or CYPE1. After incubation with horseradish peroxidase-conjugated anti-goat antibody, CYP proteins were visualized with 3',3-diaminobenzidine (10 mg/ml) and hydrogen peroxide. Relative increases over controls for each CYP isoform were determined by densitometric analysis of the proteins with the RFLP Scan 3.0 microcomputer program (Scanalytics Inc., Fairfax, VA). The CYP1A1 and CYP1A2 as well as CYP2B1 and CYP2B2 bands were considered together to calculate the relative CYP1A1/2 and CYP2B1/2 variations.
Alkoxyresorufin O-dealkylases (AROD)
Microsomal AROD activities were measured spectrofluorometrically by monitoring the formation of resorufin according to the method of Burke (Burke,M.D. et al., 1985, 1994) with some modifications: excitation and emission wavelengths were set at 520 and 585 nm, respectively. Aliquots of 10–40 µl of substrate, 1.91–1.94 ml of buffer A (50 mM Tris–HCl, 25 mM MgCl2, pH 7.6) and 10–40 µl of microsomal sample were placed in a fluorimeter cuvette and incubated at 37°C for 3 min. Reactions were started by the addition of 500 µM NADPH (20 µl of a 50 mM solution in buffer A). With a total reaction volume of 2 ml, the cuvette was then placed in the fluorimeter and the reactions followed for 3 min, recording the fluorescence reading every 15 s. Substrates were dissolved in dimethylsulfoxide as follows: 50 µM ethoxyresorufin, 0.5 mM methoxyresorufin, 1.0 mM pentoxyresorufin and 1.0 mM benzyloxyresorufin. Catalytic activities were calculated from a standard curve for resorufin (0–50 pmol/ml).
4-Nitrophenol hydroxylase (4-NPH)
Hydroxylation of 4-nitrophenol to 4-nitrocatechol was determined by a modification of the method described by Koop (1986). 4-Nitrophenol (0.2 mM) was dissolved in 50 mM Tris–HCl, 25 mM MgCl2, pH 7.4. An aliquot of 930 µl of this solution and 50 µl of microsomal sample were incubated at 37°C for 5 min. Reactions were started by adding 20 µl of 50 mM NADPH and incubation continued for 10 min. Reaction mixtures were stopped by the addition of 0.5 ml of 0.6 N perchloric acid followed by centrifugation. 4-Nitrocatechol formation was then spectrophotometrically determined in 1 ml of supernatant plus 0.1 ml of 10 N NaOH at 510 nm. A standard curve with 4-nitrocatechol (5–50 nmol/ml) was used to calculate microsomal activity.
Mutagenesis assay
Salmonella typhimurium strains TA1535, TA98 and TA100, donated by Dr B.N.Ames of the University of California, Berkeley, CA, were used for mutagenesis assays. TA1535 was used to detect the mutagenicity of CP, TA98 for B[a]P and 2-AA and TA100 for NDPA, NPYR, NDBA and NDMA. Aliquots of 100 µl of S.typhimurium overnight culture (1–2x109 cells/ml) and 500 µl of S9 mix (30 or 10% S9 fraction, 8 mM MgCl2, 33 mM KCl, 4 mM NADP, 5 mM G6P, 100 mM sodium phosphate buffer, pH 6.5) were mixed with 0.1 ml of appropriately diluted chemical solution in sterile tubes. This mixture was incubated at 37°C for 60 min, mixed with 2 ml of molten top agar at 45°C and poured onto minimal agar plates. Revertant colonies were counted after a 48 h incubation period at 37°C. B[a]P, 2AA and NDBA were dissolved in DMSO, while CP, NDPA, NPYR and NDMA were dissolved in water. The preincubation protocol was used for nitrosamines while the standard plate assay was used for B[a]P, 2-AA and CP. Samples of 10% S9 mix prepared from animals fed 6 and 24% protein diets were used as the metabolic activation system for B[a]P and 2AA, while 30% S9 mix from the same animals was used for the rest of the mutagens. Experiments were carried out at least twice and three plates were employed for each mutagen concentration.
Statistics
Student’s unpaired t-test was used to compare western blots and specific activities resulting from hepatic determinations. Mutagenic potencies were calculated from the linear portion of the dose–response curve.
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Results |
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Effects of protein restriction on body weight
The effects of the two different diets on animal body weight before and after treatment are shown in Table I
. The rate of body weight gain per day in the 6% protein group was 2.9 g, compared with 4.6 g/day gained by the 24% protein group. At the end of the experiment, a deficiency of 29% in body weight was observed in rats on the 6% protein diet.
Western blot
CYPs expression in rat liver microsomes of the hypoproteic and control groups was monitored by western blot (Figure 1). Using anti-rat CYP1A1/2 antibody resulted in the detection of one band in both groups of animals corresponding in electrophoretic mobility to CYP1A2. We also detected CYP2B1/2 and CYP2E1 bands in microsomes from both treatment groups. Densitometric analysis revealed 73, 40 and 74% decreases in CYP1A2, CYP2B1/2 and CYP2E1 apoprotein contents, respectively, in the hypoproteic diet group with respect to those in the control group.
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0.05).Enzymatic activities
Enzyme activities were significantly decreased by the hypoproteic diet (Table II
). Microsomal ethoxyresorufin O-deethylase activity (EROD) (associated with CYP1A1) was 29% of that observed in control animals, whereas methoxyresorufin O-demethylase activity (MROD) (associated with CYP1A2) decreased by 83%. With respect to the CYP2B subfamily, benzyloxyresorufin O-dealkylase (BROD) (associated with CYP2B2) activity was nine times lower in rats fed the hypoproteic diet and pentoxyresorufin O-dealkylase (PROD) (associated with CYP2B1) activity decreased by 42%. Finally, hepatic CYP2E1 activity diminished 3.4-fold with respect to the control.
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Ames test
We analyzed the mutagenicity of different model compounds in the Ames test using S9 recovered from the livers of rats fed either the hypoproteic or control diet (Table III
). With the exception of B[a]P, which showed no differences in mutagenicity regarding the source of S9, and NDPA, the mutagenicity of which was only marginally higher with the control S9, the mutagenic potencies of the majority of the mutagens tested with S9 from rats fed the control diet were more than double those with S9 from rats fed the hypoproteic diet. 2AA, NDMA and NDBA were 25-, 71- and 12-fold more mutagenic, respectively, in the assay supplemented with S9 from rats fed the control diet. The mutagenic potencies of CP and NPYR were twice as high after activation with normal S9.
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Discussion |
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Studies in rodents have shown that decreasing the protein concentration in their diets can lead to a reduction in chemical carcinogenesis and toxicity. Laboratory animals fed a normal protein diet (24%) have relatively higher sensitivity to the toxic and carcinogenic effects of chemicals compared with those fed a low protein diet (Czygan et al., 1974
; Hawrylewicz et al., 1982). Additionally, the pharmacokinetic parameters of drugs are altered in humans and rodents suffering protein/calorie malnutrition (Homeida et al., 1979; Buchanan et al., 1980; Kim and Lee, 1993; Kim et al., 1993). One explanation for the phenomena could be related to alterations in both Phase I and Phase II enzymes involved in xenobiotic metabolism.
Several protein restriction protocols have been used in rats to show that individual hepatic CYP isoforms decrease in concentration and activity (Lee et al., 1997; Cho et al., 1999; Zhang et al., 1999), however, none of these focused on exploring whether the decrease in CYP activity leads to a diminished capacity of the liver to ‘activate’ mutagens/carcinogens to their active metabolites. In this experiment we used a protein restriction protocol involving 21 day old Wistar rats fed a 6% protein diet for 45 days. This regimen produced a 29% decrease in final body weight as compared with the animals fed a 24% protein diet (Table II). Youngman (1993) showed that a smaller body size correlates with reduced proliferation and significantly decreased cell division rates in many tissues. A reduction in the body weight of rats on a 5% casein diet was also observed by Cho et al. (1999). A reduction in the amount of food consumed to a level less than that eaten by ad libitum fed animals also showed a strong correlation between dietary restriction, body weight and cancer (Hart and Turturro, 1997).
Western blot analysis did not allow us to detect CYP1A1 in normal rat hepatic microsomes, while CYP1A2, CYP2B1, CYP2B2 and CYP2E1 were constitutively expressed (Figure 1). These results agree with those reported by others showing that CYP1A1 protein is poorly expressed in liver of different animal species (Adams et al., 1985; Sesardic et al., 1990). Nevertheless, there is contradictory evidence about CYP2B1 expression. Omiecinski (1986) showed that CYP2B mRNA is not normally expressed in liver of adult male rats, while Yoo et al. (1992) demonstrated its expression in Sprague–Dawley rats. Our results showed a decrease in CYP2B1/B2 apoprotein in the liver of 11 week old Wistar rats in both groups (Figure 1).
The results from immunoblot and enzyme activity experiments demonstrated diminished CYP expression in the hypoproteic group with respect to the 24% protein group, although not all the CYP families studied were affected to the same extent (Figure 1 and Table II); CYP2B was less affected, followed by the CYP1A and CYP2E families. Similar results for CYP1A2 and CYP2E1 were found by Cho et al. (1999); they observed a 60% suppression of both immunoreactive proteins in hepatic microsomes from rats fed a 5% casein diet. Our results also agree with a 55% reduction in EROD activity and a 49% reduction in CYP2E1-associated chlorzoxazone 6-hydroxylation activity reported by Zhang et al. (1999) in liver from rats on a 5% protein diet for 3 weeks.
As far as we know, the mechanisms involved in CYP suppression by a low protein ingestion have not been described. Although DeJong and Schreiber (1987) demonstrated a 30–40% depression in the levels of albumin mRNA, transferrin, transthyretin, the ß-chain of fibrinogen and apolipoprotein E after 3 days of protein depletion in the liver of rats, data obtained by Cho et al. (1999) indicated that protein deficiency did not suppress the majority of cellular proteins and >93% of gene expression in hepatocytes was not altered. Cytokine-mediated down-regulation of CYP1A1 in Hepa1 cells has been observed by Paton and Renton (1998) and the administration of TNF-
and IL-6 showed a potent depression of the level of CYP1A1/2 activity and moderate effects on the levels of CYP2B1/2 and CYP2E1 in human and rat hepatocytes (Fukuda et al., 1992; Clark et al., 1995; Muntané-Relat et al., 1995). On the other hand, plasma concentrations of mediators of the inflammatory cascade, such as IL-6 and TNF-, are greater in children with protein/energy malnutrition compared with those observed in controls (Sauerwein et al., 1997; Malave et al., 1998). These studies taken together suggest that immune modulators altered by a protein-restricted diet can affect regulation of cytochrome P450 expression.
In order to test whether the observed modification of specific CYPs would affect mutagen activation, we used the following reference chemicals in the Ames test: NDPA, which is depropylated mainly by CYP2B1 (Shu and Hollenberg, 1990, 1996); CP, which is transformed to its 4-hydroxylated genotoxic derivative by CYP2B (Chang et al., 1993; Roy et al., 1999); NPYR and NDMA, both hydroxylated by CYP2E1 (Haag and Sipes, 1980; Garro et al., 1981); B[a]P and 2-AA, metabolized by CYP1A (Shou et al., 1994; Oda et al., 2001); NDBA, which is debutylated by rat CYP2B1 (Shu and Hollenberg, 1996).
All of the promutagens tested except B[a]P showed a reduction in mutagenic potency when hypoproteic S9 mix was used as the source of metabolic activation. The low EROD activity and the absence of CYP1A1 immunoreactive protein detected in hepatic microsomes from control and protein-deficient rats suggest that other CYPs could be involved in the marginal activation of this compound to mutagenic metabolites (Shou et al., 1994; Burczynski et al., 1999; Oda et al., 2001). Low activation of B[a]P by non-induced S9 in the Ames test has been reported previously by our laboratory (Escobar-García et al., 2001).
The dramatic reduction in CYP1A2-associated MROD activity along with reduced apoprotein detected by immunoblot paralleled the results obtained in the Ames test in that the mutagenicity of 2-AA was only 3.7% of that obtained when 24% S9 activated the promutagen (Tables II and III and Figure 1). CYP1A2 has been implicated in the metabolic activation of aromatic and heterocyclic amines in different species and it has been proposed that the levels of hepatic CYP1A2 may be an important susceptibility factor in arylamine-induced cancer in humans (Kawajiri and Hayashi, 1996).
The animal carcinogens NDPA and NDBA as well as the antineoplastic alkylating agent CP are metabolized mainly by the CYP2B family. The reductions in both CYP2B-related enzyme activities and protein content predict that 24% protein S9 will be more efficient in metabolizing CP, NDBA and NDPA to mutagenic intermediates detectable by the Ames Salmonella strains. The two former compounds induced a higher number of bacterial mutants in the presence of hepatic microsomes from well-fed rats, suggesting that animals with the lowest hepatic CYP2B content should be less efficient in producing electrophilic species from these substances.
CYP2E1 activated NDMA to its mutagenic metabolites in the Ames assay (Haag and Sipes, 1980; Garro et al., 1981). This enzyme is also involved in the -hydroxylation of NPYR, and this is reflected in an enhancement of the mutagenic potency of this compound when CYP2E1 inducers were used to obtain the S9 activation mix (Burke,D.A. et al., 1994). The decrease in activity and protein content of CYP2E1 detected in this study was also reflected in a reduction in the mutagenic potency of these two promutagens when activated by the protein-deficient S9 compared with S9 from animals fed the 24% protein diet. These data confirm previous reports by Czygan et al. (1974), who found that activation of DMNA was decreased in the presence of hepatic microsomes from mice fed a 3 or 10% protein diet compared with microsomes from mice fed a 30% protein diet. Additional evidence for the importance of CYP2E1 activity in the carcinogenic process was given by Wattenberg (1975), who showed inhibition of dimethylhydrazine carcinogenesis by pretreatment of mice with the potent CYP2E1 inhibitor disulfiram.
In conclusion, protein restriction in weanling rats produced a decrease in liver CYP-related enzyme activity and protein content of the CYP1A, CYP2B and CYP2E subfamilies, which constitute the main group of enzymes involved in the activation of environmental mutagens/carcinogens. The observed decrease in these biochemical parameters is related to a diminished capacity of hepatic microsomes to activate several promutagens in the Ames test, which is one of the most validated genotoxicity assays to predict mutagenesis.
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Acknowledgments |
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We would like to thank Dr Regina Montero for revising the English text and Dr Gerardo Arrellín and Tzipe Govezensky for their exellent technical assistance. This work was supported by a grant from CONACyT, México, no. 25377-M.
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Notes |
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4 To whom correspondence should be addressed at: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apartado Postal 70228, Ciudad Universitaria, 04510 México, D.F., México. Tel: +52 5 6 22 38 58; Fax: +52 5 6 22 38 53; Email: jjea{at}servidor.unam.mx
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Received on July 1, 2002; revised on September 13, 2002; accepted on September 24, 2002.
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