Constitutive androstane receptor (CAR) as a potential sensing biomarker of persistent organic pollutants (POPs) in aquatic mammal: Molecular characterization, expression level, and ligand profiling in Baikal seal (Pusa sibirica)

Toxicological Sciences

Volumn 94, Issue 1, 2006, Pages 57-70

  Sakai, Hiroki ^a   Iwata, Hisato ^a   Kim, Eun Young ^a   Tsydenova, Oyuna ^a,b   Miyazaki, Nobuyuki ^c   Petrov, Evgeny A ^d   Batoev, Valeriy B ^b   Tanabe, Shinsuke ^a  

^a EHIME UNIVERSITY   (Japan)

^b BAIKAL INSTITUTE OF NATURE MANAGEMENT   (Russian Federation)

^c UNIVERSITY OF TOKYO   (Japan)

^d The Eastern Siberian Scientific and Production Fisheries Center   (Russian Federation)

Author keywords

Baikal seal; Biomarker; CAR; Ligand profile

Indexed keywords

1,1 DICHLORO 2,2 BIS(4 CHLOROPHENYL)ETHYLENE; 1,4 BIS(2 [3,5 DICHLOROPYRIDYLOXY]BENZENE); 2,2',3,4,4',5,5' HEPTACHLOROBIPHENYL; 2,2',4,4',5,5' HEXACHLOROBIPHENYL; 6 (4 CHLOROPHENYL)IMIDAZO[2,1 B][1,3]THIAZOLE 5 CARBALDEHYDE O [3,4 DICHLOROBENZYL]OXIME); AMINO ACID; ANDROSTANE DERIVATIVE; BENZENE DERIVATIVE; BILE ACID; BIOLOGICAL MARKER; CHENODEOXYCHOLIC ACID; CHLORPHENOTANE; COMPLEMENTARY DNA; CONSTITUTIVE ANDROSTANE RECEPTOR; CYTOCHROME P450; CYTOCHROME P450 1A; CYTOCHROME P450 1B; CYTOCHROME P450 2B; CYTOCHROME P450 2C; DEOXYCHOLIC ACID; ESTRADIOL; ESTRONE; LIGAND; LITHOCHOLIC ACID; LUCIFERASE; MESSENGER RNA; ORGANIC COMPOUND; POLYCHLORINATED BIPHENYL DERIVATIVE; THIAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL TISSUE; ARTICLE; CELL STRAIN MCF 7; CONTROLLED STUDY; ECOTOXICOLOGY; GENE EXPRESSION REGULATION; GENE REPRESSION; GENETIC CODE; GENETIC CONSERVATION; GENETIC TRANSCRIPTION; GENETIC TRANSFECTION; HEART; HUMAN; HUMAN CELL; IN VITRO STUDY; INTESTINE; LIGAND BINDING; LIVER; MAMMAL; MOLECULAR BIOLOGY; MOLECULAR CLONING; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; OPEN READING FRAME; ORGANIC POLLUTION; PLASMID; PROTEIN EXPRESSION; PROTEIN FUNCTION; RAT; REPORTER GENE; RUSSIAN FEDERATION; SEAL; SEQUENCE HOMOLOGY; TRANSACTIVATION; WATER POLLUTANT; WATER POLLUTION INDICATOR;

AMINO ACID SEQUENCE; ANIMALS; BIOLOGICAL MARKERS; CELL LINE, TUMOR; CLONING, MOLECULAR; DDT; DICHLORODIPHENYL DICHLOROETHYLENE; DNA, COMPLEMENTARY; GENE EXPRESSION PROFILING; HUMANS; LIGANDS; LUCIFERASES; MICE; MOLECULAR SEQUENCE DATA; PHOCA; POLYCHLORINATED BIPHENYLS; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECOMBINANT FUSION PROTEINS; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RNA, MESSENGER; SEQUENCE ANALYSIS, DNA; SEQUENCE HOMOLOGY, AMINO ACID; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC; TRANSFECTION; WATER POLLUTANTS, CHEMICAL;

MAMMALIA; PHOCA SIBIRICA; RODENTIA;

EID: 33749588494     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfl088     Document Type: Article

References (71)

1. Assem, M., Schuetz, E. G., Leggas, M., Sun, D., Yasuda, K., Reid, G., Zelcer, N., Adachi, M., Strom, S., Evans, R. M., et al. (2004). Interaction between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice. J. Biol. Chem. 279, 22250-22257.
2. Baes, M., Gulick, T., Choi, H.-S., Martinoli, M. G., Simha, D., and Moore, D. D. (1994). A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol. Cell Biol. 14, 1544-1552.
3. Chang, T. K. H., Bandiera, S. M., and Chen, J. (2003). Constitutive androstane receptor and pregnane X receptor gene expression in human liver: Interindividual variability and correlation with CYP2B6 mRNA levels. Drug Metab. Disp. 31, 7-10.
4. Choi, H.-S., Chung, M., Tzameli, I., Simha, D., Lee, Y. K., Seol, W., and Moore, D. D. (1997). Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J. Biol. Chem. 272, 23565-23571.
5. Connor, K., Safe, S., Jefcoate, C. R., and Larsen, M. (1995). Structure-dependent induction of CYP2B by polychlorinated biphenyl congeners in female Sprague-Dawley rats. Biochem. Pharmacol. 50, 1913-1920.
6. Craft, E. S., DeVito, M. J., and Crofton, K. M. (2002). Comparative responsiveness of hypothyroxinemia and hepatic enzyme induction in Long-Evans rats versus C57BL/6J mice exposed to TCDD-like and phenobarbital-like polychlorinated biphenyl congeners. Toxicol. Sci. 68, 372-380.
7. Dai, D., Cao, Y., Falls, G., Levi, P. E., Hodgson, E., and Rose, R. L. (2001). Modulation of mouse P450 isoforms CYP1A2, CYP2B10, CYP2E1, and CYP3A by the environmental chemicals mirex, 2,2-bis(p-chlorophenyl)-1, 1-dichloroethylene, vinclozolon, and flutamide. Pestic. Biochem. Physiol. 70, 127-141.
8. Ferguson, S. S., Lecluyse, E. L., Negishi, M., and Goldstein, J. A. (2002). Regulation of human CYP2C9 by the constitutive androstane receptor: Discovery of a new distal binding site. Mol. Pharmacol. 62, 737-746.
9. Fischer, S., Beuers, U., Spengler, U., Zwiebel, F. M., and Koebe, H.-G. (1996). Hepatic levels of bile acids in end-stage chronic cholestatic liver disease. Clin. Chim. Acta 251, 173-186.
10. Forman, B. M., Tzameli, I., Choi, H.-S., Chen, J., Simha, D., Seol, W., Evans, R. M., and Moore, D. D. (1998). Androstane metabolites bind to and deactivate the nuclear receptor CAR-β. Nature 395, 612-615.
11. Frank, C., Gonzalez, M. M., Oinonen, C., Dunlop, T. W., and Carlberg, C. (2003). Characterization of DNA complexes formed by the nuclear receptor constitutive androstane receptor. J. Biol. Chem. 278, 43299-43310.
12. Gerbal-Chaloin, S., Daujat, M., Pascussi, J.-M., Pichard-Garcia, L., Vilarem, M.-J., and Maurel, P. (2002). Transcriptional regulation of CYP2C9 gene. J. Biol. Chem. 277, 209-217.
13. Goodwin, B., Hodgson, E., D'costa, D. J., Robertson, G. R., and Liddle, C. (2002). Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Mol. Pharmacol. 62, 359-365.
14. Goodwin, B., Hodgson, E., and Liddle, C. (1999). The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol. Pharmacol. 56, 1329-1339.
15. Goodwin, B., Moore, L. B., Stoltz, C. M., McKee, D. D., and Kliewer, S. A. (2001). Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol. Pharmacol. 60, 427-431.
16. Guo, G. L., Lambert, G., Negishi, M., Ward, J. M., Brewer, H. B., Kliewer, S. A., Gonzalez, F. J., and Sinal, C. J. (2003). Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. J. Biol. Chem. 278, 45062-45071.
17. Handschin, C., and Meyer, U. A. (2005). Regulatory network of lipid-sensing nuclear receptors: Roles for CAR, PXR, LXR, and FXR. Arch. Biochem. Biophys. 433, 387-396.
18. Haraguchi, K., Athanasiadou, M., Bergman, A., Hovander, L., and Jensen, S. (1992). PCB and PCB methyl sulfones in selected group of seals from Swedish waters. AMBIO 21, 546-549.
19. Heder, A. F., Hirsch-Ernst, K. I., Bauer, D., Kahl, G. F., and Desel, H. (2001). Induction of cytochrome P450 2B1 by pyrethroids in primary rat hepatocyte cultures. Biochem. Pharmacol. 62, 71-79.
20. Honkakoski, P., Moore, R., Washburn, K. A., and Negishi, M. (1998). Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the CYP2B10 gene. Mol. Pharmacol. 53, 597-601.
21. Huang, W., Zhang, J., Chua, S. S., Qatanani, M., Han, Y., Granata, R., and Moore, D. D. (2003). Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc. Natl. Acad. Sci. U.S.A. 100, 4156-4161.
22. Huang, W., Zhang, J., Washington, M., Liu, J., Parant, J. M., Lozano, G., and Moore, D. D. (2005). Xenobiotic stress induces hepatomegaly and liver tumors via nuclear receptor constitutive androstane receptor. Mol. Endocrinol. 19, 1646-1653.
23. Iwata, H., Kim, E.-Y., Sakamoto, T., Ebisuda. K., Okajima, Y., Watanabe, M., Tanabe, S., Amano, M., and Miyazaki, N. (2003). Implication of AhR- and CYP1A/1B-mediated effects by PCDDs/DFs and coplanar PCBs in Baikal seal. Organohalogen Compd. 62, 216-219.
24. Iwata, H., Tanabe, S., Ueda, K., and Tatsukawa, R. (1995). Persistent organochlorine residues in air, water, sediment, and soils from the Lake Baikal region, Russia. Environ. Sci. Technol. 29, 792-801.
25. Iwata, H., Watanabe, M., Okajima, Y., Tanabe, S., Amano, M., Miyazaki, N., and Petrov, E. A. (2004). Toxicokinetics of PCDD, PCDF, and coplanar PCB congeners in Baikal seals, Pusa sibirica: Age-related accumulation, maternal transfer, and hepatic sequestration. Environ. Sci. Technol. 38, 3505-3513.
26. Iwata, H., Yoshinari, K., Negishi, M., and Stegeman, J. J. (2002). Species-specific responses of constitutively active receptor (CAR)-CYP2B coupling: Lack of CYP2B inducer-responsive nuclear translocation of CAR in marine teleost, scup (Stenotomus chrysops). Comp. Biochem. Physiol. C 131, 501-510.
27. Johansson, M., Nilsson, S., and Lund, B.-O. (1998). Interactions between methysulfonyl PCBs and the glucocorticoid receptor. Environ. Health Perspect. 106, 769-772.
28. Jyrkkärinne, J., Mäkinen, J., Gynther, J., Savolainen, H., Poso, A., and Honkakoski, P. (2003). Molecular determinants of steroid inhibition for the mouse constitutive androstane receptor. J. Med. Chem. 46, 4687-4695.
29. Kawamoto, T., Kakizaki, S., Yoshinari, K., and Negishi, M. (2000). Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse CYP2B10 gene. Mol. Endocrinol. 14, 1897-1905.
30. Kawamoto, T., Sueyoshi, T, Zelko, I., Moore, R., Washburn, K., and Negishi, M. (1999). Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol. Cell Biol. 19, 6318-6322.
31. Kim, E.-Y., Hahn, M. E., Iwata, H., Tanabe, S., and Miyazaki, N. (2002). cDNA cloning of an aryl hydrocarbon receptor from Baikal seal (Phoca sibirica). Mar. Environ. Res. 54, 285-289.
32. Kim, E.-Y., Iwata, H., Suda, T., Tanabe, S., Amano, M., Miyazaki, N., and Petrov, E. A. (2005). Aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) expression in Baikal seal (Pusa sibirica) and association with 2,3,7,8-TCDD toxic equivalents and CYP1 expression levels. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 141, 281-291.
33. Kobayashi, K., Sueyoshi, T., Inoue, K., Moore, R., and Negishi, M. (2003). Cytoplasmic accumulation of the nuclear receptor CAR by a tetratric opeptide repeat protein in HepG2 cells. Mol. Pharmacol. 64, 1069-1075.
34. Kodama, S., Koike, C., Negishi, M., and Yamamoto, Y. (2004). Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol. Cell. Biol. 24, 7931-7940.
35. Krasowski, M. D., Yasuda, K., Hagey, L. R., and Schuetz, E. G. (2005). Evolution of the pregnane X receptor: Adaptation to cross-species differences in biliary bile salts. Mol. Endocrinol. 19, 1720-1739.
36. Kubota, A., Iwata, H., Tanabe, S., Yoneda, K., and Tobata S. (2005). Hepatic CYP1A induction by dioxin-like compounds, and congener-specific metabolism and sequestration in wild common cormorants from Lake Biwa, Japan. Environ. Sci. Technol. 39, 3611-3619.
37. Lee, A. J., Cai, M. X., Thomas, P. E., Conney, A. H., and Zhu, B. T. (2003). Characterization of the oxidative metabolites of 17β-estradiol and estrone formed by 15 selectively expressed human cytochrome P450 isoforms. Endocrinology 144, 3382-3398.
38. Lemaire, G., de Sousa, G., and Rahmani, R. (2004). A PXR reporter gene assay in a stable cell culture system: CYP3A4 and CYP2B6 induction by pesticides. Biochem. Pharmacol. 68, 2347-2358.
39. Maglich, J. M., Parks, D. J., Moore, L. B., Collins, J. L., Goodwin, B., Billin, A. N., Stoltz, C. A., Kliewer, S. A., Lambert, M. H., Willson, T. M., et al. (2003). Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J. Biol. Chem. 278, 17277-17283.
40. Maglich, J. M., Stoltz, C. M., Goodwin, B., Hawkins-Brown, D., Moore, J. T., and Kliewer, S. A. (2002). Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol. Pharmacol. 62, 638-646.
41. McJunkin, B., Fromm, H., Sarva, R. P., and Amin, P. (1981). Factors in the mechanism of diarrhea in bile acid malabsorption: Fecal pH - a key determinant. Gastroenterology 80, 1454-1464.
42. Medina-Diaz, I. M., and Elizondo, G. (2005). Transcriptional induction of CYP3A4 by o,p′-DDT in HepG2 cell. Toxicol. Lett. 157, 41-47.
43. Min, G., Kemper, J. K., and Kemper, B. (2002). Glucocorticoid receptor-interacting protein 1 mediates ligand-independent nuclear translocation and activation of constitutive androstane receptor in vivo. J. Biol. Chem. 277, 26356-26363.
44. Moore, L. B., Maglich, J. M., McKee, D. D., Wisely, B., Willson, T. M., Kliewer, S. A., Lambert, M. H., and Moore, J. T. (2002). Pregnane X receptor (PXR), constitutive androstane receptors (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. Mol. Endocrinol. 16, 977-986.
45. Moore, L. B., Parks, D. J., Jones, S. A., Bledsoe, R. K., Consler, T. G., Stimmel, J. B., Goodwin, B., Liddle, C., Blanchard, S. G., Willson, T. M., et al. (2000). Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. Biol. Chem. 275, 15122-15127.
46. Nakata, H., Tanabe, S., Tatsukawa, R., Amano, M., Miyazaki, N., and Petrov, E. A. (1995). Persistent organochlorine residues and their accumulation kinetics in Baikal seal (Phoca sibirica) from Lake Baikal, Russia. Environ. Sci. Technol. 29, 2877-2885.
47. Nakata, H., Tanabe, S., Tatsukawa, R., Amano, M., Miyazaki, N., and Petrov, E. A. (1997). Bioaccumulation profiles of polychlorinated biphenyls including coplanar congeners and possible toxicological implications in Baikal seal (Phoca sibirica). Environ. Pollut. 95, 57-65.
48. Nims, R. W., and Lubet, R. A. (1995). Induction of cytochrome P-450 in the Norway rat, Rattus norvegicus, following exposure to potential environmental contaminants. J. Toxicol. Environ. Health 46, 271-292.
49. Pascussi, J. M., Coniat, M. B.-L., Maurel, P., and Vilarem, M.-J. (2003). Transcriptional analysis of the orphan nuclear receptor constitutive androstane receptor (NR1I3) gene promoter: Identification of a distal glucocorticoid response element. Mol. Endocrinol. 17, 42-55.
50. Qatanani, M., Zhang, J., and Moore, D. D. (2005). Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism. Endocrinology 146, 995-1002.
51. Quack, M., and Carlberg, C. (2000). Ligand-triggered stabilization of vitamin D receptor/retinoid X receptor heterodimer conformations on DR4-type response elements. J. Mol. Biol. 296, 743-756.
52. Sakai, H., Iwata, H., Kim, E.-Y., Tanabe, S., and Baba, N. (2004). Identification of constitutive androstane receptor cDNA in northern fur seal (Callorhinus ursinus). Mar. Environ. Res. 58, 107-111.
53. Shan, L., Vincent, J., Brunzelle, J. S., Dussault, I., Lin, M., Ianculescu, I., Sherman, M. A., Forman, B. M., and Fernandez, E. J. (2004). Structure of the murine constitutive androstane receptor complexed to androstenol: A molecular basis for inverse agonism. Mol. Cell 16, 907-917.
54. Sueyoshi, T., Kawamoto, T., Zelko, I., Honkakoski, P., and Negishi, M. (1999). The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J. Biol. Chem. 274, 6043-6046.
55. Sugatani, J., Kojima, H., Ueda, A., Kakizaki, S., Yoshinari, K., Gong, Q.-H., Owens, I. S., Negishi, M., and Sueyoshi, T. (2001). The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 33, 1232-1238.
56. Suino, K., Peng, L., Reynolds, R., Li, Y., Cha, J.-Y., Repa, J. J., Kliewer, S. A., and Xu, H. E. (2004). The nuclear xenobiotic receptor CAR: Structural determinants of constitutive activation and heterodimerization. Mol. Cell 16, 893-905.
57. Tanabe, S., Iwata, H., and Tatsukawa, R. (1994). Global contamination by persistent organochlorines and their ecotoxicological impact on marine mammals. Sci. Total Environ. 154, 163-177.
58. Tanabe, S., Niimi, S., Minh, T. B., Miyazaki, N., and Petrov, E. A. (2003). Temporal trends of persistent organochlorine contamination in Russia: A case study of Baikal and Caspian seal. Arch. Environ. Contam. Toxicol. 44, 533-545.
59. Tzameli, I., Pissios, P., Schuetz, E. G., and Moore, D. D. (2000). The xenobiotic compounds 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Mol. Cell Biol. 20, 2951-2958.
60. Ueda, A., Hamadeh, H. K., Webb, H. K., Yamamoto, Y., Sueyoshi, T., Afshari, C. A., Lehmann, J. M., and Negishi, M. (2002). Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol. Pharmacol. 61, 1-6.
61. Vezina, C. M., Walker, N. J., and Olson, J. R. (2004). Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: Effect on hepatic gene expression. Environ. Health Perspect. 112, 1636-1644.
62. Wagner, M., Halilbasic, E., Marschall, H.-U., Zollner, G., Fickert, P., Langner, C., Zatloukal, K., Denk, H., and Trauner, M. (2005). CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology 42, 420-430.
63. Watanabe, M., Tanabe, S., Miyazaki, N., Petrov, E. A., and Jarman, W. M. (1999). Contamination of tris(4-chlorophenyl)methane and tris(4-chlorophenyl)methanol in marine mammals from Russia and Japan: Body distribution, bioaccumulation and contamination status. Mar. Pollut. Bull. 39, 393-398.
64. Waxman, D. J. (1999). P450 gene induction by structurally diverse xenochemicals: Central role of nuclear receptors CAR, PXR, and PPAR. Arch. Biochem. Biophys. 369, 11-23.
65. Wei, P., Zhang, J., Dowhan, D. H., Han, Y., and Moore, D. D. (2002). Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenomics J. 2, 117-126.
66. Wyde, M. E., Bartolucci, E., Ueda, A., Zhang, H., Yan, B., Negishi, M., and You, L. (2003). The environmental pollutant 1, 1-dichloro-2,2-bis(p-chlorophenyl)ethylene induces rat hepatic cytochrome P450 2B and 3A expression through the constitutive androstane receptor and pregnane X receptor. Mol. Pharmacol. 64, 474-481.
67. Xie, W., Barwick, J. L., Simon, C. M., Pierce, A. M., Safe, S., Blumberg, B., Guzelian, P. S., and Evans, R. M. (2000). Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Gene Dev. 14, 3014-3023.
68. Yoshinari, K., Kobayashi, K., Moore, R., Kawamoto, T., and Negishi, M. (2003). Identification of the nuclear receptor CAR: HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital. FEBS Lett. 548, 17-20.
69. Yoshinari, K., Sueyoshi, T., Moore, R., and Negishi, M. (2001). Nuclear receptor CAR as a regulatory factor for the sexually dimorphic induction of CYP2B1 gene by phenobarbital in rat livers. Mol. Pharmacol. 59, 278-284.
70. You, L., Chan, S. K., Bruce, J. M., Archibeque-Engle, S., Casanova, M., Corton, J. C., and Heck, H. d'A. (1999). Modulation of testosterone-metabolizing hepatic cytochrome P-450 enzymes in developing Sprague-Dawley rats following in utero exposure to p,p′-DDE. Toxicol. Appl. Pharmacol. 158, 197-205.
71. Zelko, I., Sueyoshi, T., Kawamoto, T., Moore, R., and Negishi, M. (2001). The peptide near C terminus regulates receptor CAR nuclear translocation induced by xenochemicals in mouse liver. Mol. Cell Biol. 21, 2838-2846.