Human cytochrome P450 2E1 mutations that alter mitochondrial targeting efficiency and susceptibility to ethanol-induced toxicity in cellular models

Journal of Biological Chemistry

Volumn 288, Issue 18, 2013, Pages 12627-12644

  Bansal, Seema ^a   Anandatheerthavarada, Hindupur K ^a   Prabu, Govindaswamy K ^a   Milne, Ginger L ^b   Martin, Martha V ^b   Guengerich, F Peter ^b   Avadhani, Narayan G ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME C OXIDASE; ENDOPLASMIC RETICULUM; MITOCHONDRIAL DYSFUNCTION; PROTEIN CODING REGIONS; REACTIVE OXYGEN SPECIES; REGULATORY REGIONS; SUBCELLULAR DISTRIBUTION; SUBCELLULAR LOCALIZATIONS;

CELL MEMBRANES; PROTEINS; TOXICITY;

MITOCHONDRIA;

ALCOHOL; CYTOCHROME C OXIDASE; CYTOCHROME P450 2E1;

AMINO TERMINAL SEQUENCE; ANIMAL CELL; ARTICLE; CELLULAR DISTRIBUTION; CONFOCAL MICROSCOPY; CONTROLLED STUDY; CYP2E1 GENE; CYTOKINE PRODUCTION; ENDOPLASMIC RETICULUM; ENZYME ACTIVITY; GENE; GENE MUTATION; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; HUMAN; HUMAN CELL; HUMAN TISSUE; LIPID PEROXIDATION; LIVER TOXICITY; MEMBRANE POTENTIAL; MITOCHONDRION; NONHUMAN; POINT MUTATION; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN STABILITY; PROTEIN TARGETING; REAL TIME POLYMERASE CHAIN REACTION; SITE DIRECTED MUTAGENESIS;

ALCOHOL; ANTIOXIDANTS; CYTOCHROME P450; DRUG METABOLISM; FREE RADICALS; GENETIC POLYMORPHISM; MITOCHONDRIA;

AMINO ACID SUBSTITUTION; ANIMALS; CENTRAL NERVOUS SYSTEM DEPRESSANTS; CERCOPITHECUS AETHIOPS; COS CELLS; CYTOCHROME P-450 CYP2E1; ETHANOL; HEP G2 CELLS; HUMANS; LIVER; MITOCHONDRIA; MITOCHONDRIAL PROTEINS; MODELS, BIOLOGICAL; MUTATION, MISSENSE; OXYGEN CONSUMPTION; PROTEIN TRANSPORT;

EID: 84877106969     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M113.452367     Document Type: Article

References (84)

1. Bondy, S. C. (1992) Ethanol toxicity and oxidative stress. Toxicol. Lett. 63, 231-241
2. Cederbaum, A. I., Lu, Y., and Wu, D. (2009) Role of oxidative stress in alcohol-induced liver injury. Arch. Toxicol. 83, 519-548
3. Fernández-Checa, J. C., Kaplowitz, N., Colell, A., and García-Ruiz, C. (1997) Oxidative stress and alcoholic liver disease. Alcohol Health Res. World 21, 321-324
4. Koop, D. R. (2006) Alcohol metabolism's damaging effects on the cell. A focus on reactive oxygen generation by the enzyme cytochrome P450 2E1. Alcohol Res. Health 29, 274-280
5. Nordmann, R., Ribière, C., and Rouach, H. (1992) Implication of free radical mechanisms in ethanol-induced cellular injury. Free Radic. Biol. Med. 12, 219-240
6. Caro, A. A., and Cederbaum, A. I. (2004) Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu. Rev. Pharmacol. Toxicol. 44, 27-42 (Pubitemid 38263832)
7. Lieber, C. S. (1994) Susceptibility to alcohol-related liver injury. Alcohol Alcohol. Suppl. 2, 315-326
8. Lieber, C. S. (1997) Cytochrome P-4502E1. Its physiological and pathological role. Physiol. Rev. 77, 517-544
9. Guengerich, F. P., Kim, D. H., and Iwasaki, M. (1991) Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem. Res. Toxicol. 4, 168-179
10. Lieber, C. S. (2004) CYP2E1. From ASH to NASH. Hepatol. Res. 28, 1-11
11. Lu, Y., and Cederbaum, A. I. (2008) CYP2E1 and oxidative liver injury by alcohol. Free Radic. Biol. Med. 44, 723-738
12. Dey, A., and Cederbaum, A. I. (2006) Alcohol and oxidative liver injury. Hepatology 43, S63-S74
13. Dicker, E., and Cederbaum, A. I. (1988) Increased oxygen radical-dependent inactivation of metabolic enzymes by liver microsomes after chronic ethanol consumption. FASEB J. 2, 2901-2906
14. Gonzalez, F. J. (2005) Role of cytochromes P450 in chemical toxicity and oxidative stress. Studies with CYP2E1. Mutat. Res. 569, 101-110
15. Koop, D. R., and Tierney, D. J. (1990) Multiple mechanisms in the regulation of ethanol-inducible cytochrome P450IIE1. BioEssays 12, 429-435
16. Boveris, A., Fraga, C. G., Varsavsky, A. I., and Koch, O. R. (1983) Increased chemiluminescence and superoxide production in the liver of chronically ethanol-treated rats. Arch. Biochem. Biophys. 227, 534-541 (Pubitemid 14218143)
17. Ekström, G., and Ingelman-Sundberg, M. (1989) Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1). Biochem. Pharmacol. 38, 1313-1319 (Pubitemid 19101961)
18. Rashba-Step, J., Turro, N. J., and Cederbaum, A. I. (1993) ESR studies on the production of reactive oxygen intermediates by rat liver microsomes in the presence of NADPH or NADH. Arch. Biochem. Biophys. 300, 391-400 (Pubitemid 23225762)
19. French, S. W., Morimoto, M., Reitz, R. C., Koop, D., Klopfenstein, B., Estes, K., Clot, P., Ingelman-Sundberg, M., and Albano, E. (1997) Lipid peroxidation, CYP2E1 and arachidonic acid metabolism in alcoholic liver disease in rats. J. Nutr. 127, 907S-911S (Pubitemid 27209466)
20. Koop, D. R., and Coon, M. J. (1986) Ethanol oxidation and toxicity. Role of alcohol P-450 oxygenase. Alcohol Clin. Exp. Res. 10, 44S-49S
21. Koop, D. R. (1992) Oxidative and reductive metabolism by cytochrome P450 2E1. FASEB J. 6, 724-730
22. Bhagwat, S. V., Boyd, M. R., and Ravindranath, V. (2000) Multiple forms of cytochrome P450 and associated monooxygenase activities in human brain mitochondria. Biochem. Pharmacol. 59, 573-582 (Pubitemid 30045595)
23. 2-terminally truncated catalytically active form of rat cytochrome P450 2E1 targeted to liver mitochondria(1). FEBS Lett. 460, 309-314
24. Robin, M. A., Anandatheerthavarada, H. K., Biswas, G., Sepuri, N. B., Gordon, D. M., Pain, D., and Avadhani, N. G. (2002) Bimodal targeting of microsomal CYP2E1 to mitochondria through activation of an N-terminal chimeric signal by cAMP-mediated phosphorylation. J. Biol. Chem. 277, 40583-40593 (Pubitemid 35215638)
25. Robin, M. A., Sauvage, I., Grandperret, T., Descatoire, V., Pessayre, D., and Fromenty, B. (2005) Ethanol increases mitochondrial cytochrome P450 2E1 in mouse liver and rat hepatocytes. FEBS Lett. 579, 6895-6902 (Pubitemid 41773706)
26. Robin, M. A., Anandatheerthavarada, H. K., Fang, J. K., Cudic, M., Otvos, L., and Avadhani, N. G. (2001) Mitochondrial targeted cytochrome P450 2E1 (P450 MT5) contains an intact N terminus and requires mitochondrial specific electron transfer proteins for activity. J. Biol. Chem. 276, 24680-24689
27. Bansal, S., Srinivasan, S., Anandasadagopan, S., Chowdhury, A. R., Selvaraj, V., Kalyanaraman, B., Joseph, J., and Avadhani, N. G. (2012) Additive effects of mitochondrion-targeted cytochrome CYP2E1 and alcohol toxicity on cytochrome c oxidase function and stability of respirosome complexes. J. Biol. Chem. 287, 15284-15297
28. Bansal, S., Liu, C. P., Sepuri, N. B., Anandatheerthavarada, H. K., Selvaraj, V., Hoek, J., Milne, G. L., Guengerich, F. P., and Avadhani, N. G. (2010) Mitochondria-targeted cytochrome P450 2E1 induces oxidative damage and augments alcohol-mediated oxidative stress. J. Biol. Chem. 285, 24609-24619
29. Knockaert, L., Descatoire, V., Vadrot, N., Fromenty, B., and Robin, M. A. (2011) Mitochondrial CYP2E1 is sufficient to mediate oxidative stress and cytotoxicity induced by ethanol and acetaminophen. Toxicol. In Vitro 25, 475-484
30. Chacko, B. K., Srivastava, A., Johnson, M. S., Benavides, G. A., Chang, M. J., Ye, Y., Jhala, N., Murphy, M. P., Kalyanaraman, B., and Darley-Usmar, V. M. (2011) Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis. Hepatology 54, 153-163
31. Uematsu, F., Kikuchi, H., Motomiya, M., Abe, T., Sagami, I., Ohmachi, T., Wakui, A., Kanamaru, R., and Watanabe, M. (1991) Association between restriction fragment length polymorphism of the human cytochrome P450IIE1 gene and susceptibility to lung cancer. Jpn. J. Cancer Res. 82, 254-256
32. Hayashi, S., Watanabe, J., and Kawajiri, K. (1991) Genetic polymorphisms in the 5′-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene. J. Biochem. 110, 559-565
33. Vodicka, P., Soucek, P., Tates, A. D., Dusinska, M., Sarmanova, J., Zamecnikova, M., Vodickova, L., Koskinen, M., de Zwart, F. A., Natarajan, A. T., and Hemminki, K. (2001) Association between genetic polymorphisms and biomarkers in styrene-exposed workers. Mutat. Res. 482, 89-103 (Pubitemid 32787086)
34. Marchand, L. L., Wilkinson, G. R., and Wilkens, L. R. (1999) Genetic and dietary predictors of CYP2E1 activity. A phenotyping study in Hawaii Japanese using chlorzoxazone. Cancer Epidemiol. Biomarkers Prev. 8, 495-500 (Pubitemid 29270332)
35. Uematsu, F., Kikuchi, H., Motomiya, M., Abe, T., Ishioka, C., Kanamaru, R., Sagami, I., and Watanabe, M. (1992) Human cytochrome P450IIE1 gene. DraI polymorphism and susceptibility to cancer. Tohoku J. Exp. Med. 168, 113-117
36. Wu, X., Shi, H., Jiang, H., Kemp, B., Hong, W. K., Delclos, G. L., and Spitz, M. R. (1997) Associations between cytochrome P4502E1 genotype, mutagen sensitivity, cigarette smoking and susceptibility to lung cancer. Carcinogenesis 18, 967-973 (Pubitemid 28132341)
37. Wu, X., Amos, C. I., Kemp, B. L., Shi, H., Jiang, H., Wan, Y., and Spitz, M. R. (1998) Cytochrome P450 2E1 DraI polymorphisms in lung cancer in minority populations. Cancer Epidemiol. Biomarkers Prev. 7, 13-18 (Pubitemid 28087136)
38. Shields, P. G., Ambrosone, C. B., Graham, S., Bowman, E. D., Harrington, A. M., Gillenwater, K. A., Marshall, J. R., Vena, J. E., Laughlin, R., Nemoto, T., and Freudenheim, J. L. (1996) A cytochrome P4502E1 genetic polymorphism and tobacco smoking in breast cancer. Mol. Carcinog. 17, 144-150 (Pubitemid 26408189)
39. Farker, K., Lehmann, M. H., Oelschlägel, B., Haerting, J., Hoffmann, A., Janitzky, V., and Schubert, J. (1998) Impact of CYP2E1 genotype in renal cell and urothelial cancer patients. Exp. Toxicol. Pathol. 50, 425-431 (Pubitemid 28439494)
40. el-Zein, R., Zwischenberger, J. B., Wood, T. G., Abdel-Rahman, S. Z., Brekelbaum, C., and Au, W. W. (1997) Combined genetic polymorphism and risk for development of lung cancer. Mutat. Res. 381, 189-200 (Pubitemid 28015414)
41. Lin, D. X., Tang, Y. M., Peng, Q., Lu, S. X., Ambrosone, C. B., and Kadlubar, F. F. (1998) Susceptibility to esophageal cancer and genetic polymorphisms in glutathione S-transferases T1, P1, and M1 and cytochrome P450 2E1. Cancer Epidemiol. Biomarkers Prev. 7, 1013-1018 (Pubitemid 28514102)
42. Kongruttanachok, N., Sukdikul, S., Setavarin, S., Kerekhjanarong, V., Supiyaphun, P., Voravud, N., Poovorawan, Y., and Mutirangura, A. (2001) Cytochrome P450 2E1 polymorphism and nasopharyngeal carcinoma development in Thailand: a correlative study. BMC Cancer 1, 4
43. Liu, S., Park, J. Y., Schantz, S. P., Stern, J. C., and Lazarus, P. (2001) Elucidation of CYP2E1 5′ regulatory RsaI/Pstl allelic variants and their role in risk for oral cancer. Oral Oncol. 37, 437-445 (Pubitemid 32480281)
44. Ingelman-Sundberg, M., and Rodriguez-Antona, C. (2005) Pharmacogenetics of drug-metabolizing enzymes. Implications for a safer and more effective drug therapy. Philos. Trans. R. Soc. Lond. B Biol. Sci. 360, 1563-1570
45. Konishi, T., Calvillo, M., Leng, A. S., Feng, J., Lee, T., Lee, H., Smith, J. L., Sial, S. H., Berman, N., French, S., Eysselein, V., Lin, K. M., and Wan, Y. J. (2003) The ADH3*2 and CYP2E1 c2 alleles increase the risk of alcoholism in Mexican American men. Exp. Mol. Pathol. 74, 183-189 (Pubitemid 36438668)
46. Sun, F., Tsuritani, I., and Yamada, Y. (2002) Contribution of genetic polymorphisms in ethanol-metabolizing enzymes to problem drinking behavior in middle-aged Japanese men. Behav. Genet. 32, 229-236 (Pubitemid 34913073)
47. Hu, Y., Oscarson, M., Johansson, I., Yue, Q. Y., Dahl, M. L., Tabone, M., Arincò, S., Albano, E., and Ingelman-Sundberg, M. (1997) Genetic polymorphism of human CYP2E1. Characterization of two variant alleles. Mol. Pharmacol. 51, 370-376 (Pubitemid 27118471)
48. Addya, S., Anandatheerthavarada, H. K., Biswas, G., Bhagwat, S. V., Mullick, J., and Avadhani, N. G. (1997) Targeting of NH2-terminal-processed microsomal protein to mitochondria. A novel pathway for the biogenesis of hepatic mitochondrial P450MT2. J. Cell Biol. 139, 589-599 (Pubitemid 27485826)
49. Sangar, M. C., Anandatheerthavarada, H. K., Tang, W., Prabu, S. K., Martin, M. V., Dostalek, M., Guengerich, F. P., and Avadhani, N. G. (2009) Human liver mitochondrial cytochrome P450 2D6. Individual variations and implications in drug metabolism. FEBS J. 276, 3440-3453
50. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951) Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265-275
51. Hegde, R. S., Voigt, S., and Lingappa, V. R. (1998) Regulation of protein topology by trans-acting factors at the endoplasmic reticulum. Mol. Cell 2, 85-91 (Pubitemid 128378969)
52. Anandatheerthavarada, H. K., Biswas, G., Mullick, J., Sepuri, N. B., Otvos, L., Pain, D., and Avadhani, N. G. (1999) Dual targeting of cytochrome P4502B1 to endoplasmic reticulum and mitochondria involves a novel signal activation by cyclic AMP-dependent phosphorylation at Ser128. EMBO J. 18, 5494-5504 (Pubitemid 29486369)
53. Koch, J. A., and Waxman, D. J. (1991) P450 phosphorylation in isolated hepatocytes and in vivo. Methods Enzymol. 206, 305-315
54. Gasser, S. M., Daum, G., and Schatz, G. (1982) Import of proteins into mitochondria. Energy-dependent uptake of precursors by isolated mitochondria. J. Biol. Chem. 257, 13034-13041
55. Bhat, N. K., and Avadhani, N. G. (1984) The transport and processing of carbamyl phosphate synthetase-I in mouse hepatic mitochondria. Biochem. Biophys. Res. Commun. 118, 514-522
56. Laemmli, U. K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680-685
57. Omura, T., and Sato, R. (1964) The carbon monoxide-binding pigment of liver microsomes. II. Solubilization, purification, and properties. J. Biol. Chem. 239, 2379-2385
58. Omura, T., and Sato, R. (1964) The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J. Biol. Chem. 239, 2370-2378
59. Guengerich, F. P., Dannan, G. A., Wright, S. T., Martin, M. V., and Kaminsky, L. S. (1982) Purification and characterization of liver microsomal cytochromes P-450. Electrophoretic, spectral, catalytic, and immunochemical properties and inducibility of eight isozymes isolated from rats treated with phenobarbital or β-naphthoflavone. Biochemistry 21, 6019-6030 (Pubitemid 13184201)
60. Guengerich, F. P., Dannan, G. A., Wright, S. T., Martin, M. V., and Kaminsky, L. S. (1982) Purification and characterization of microsomal cytochrome P-450s. Xenobiotica 12, 701-716 (Pubitemid 13176353)
61. Eliasson, E., Mkrtchian, S., and Ingelman-Sundberg, M. (1992) Hormone- and substrate-regulated intracellular degradation of cytochrome P450 (2E1) involving MgATP-activated rapid proteolysis in the endoplasmic reticulum membranes. J. Biol. Chem. 267, 15765-15769
62. Eliasson, E., Gardner, I., Hume-Smith, H., de Waziers, I., Beaune, P., and Kenna, J. G. (1998) Interindividual variability in P450-dependent generation of neoantigens in halothane hepatitis. Chem. Biol. Interact. 116, 123-141 (Pubitemid 29023158)
63. Yamazaki, H., Inui, Y., Yun, C. H., Guengerich, F. P., and Shimada, T. (1992) Cytochrome P450 2E1 and 2A6 enzymes as major catalysts for metabolic activation of N-nitrosodialkylamines and tobacco-related nitrosamines in human liver microsomes. Carcinogenesis 13, 1789-1794
64. 2-terminal truncated cytochrome P4501A1 in rat brain during chronic treatment with β-naphthoflavone. A role in the metabolism of neuroactive drugs. J. Biol. Chem. 275, 34415-34423
65. LeBel, C. P., Ischiropoulos, H., and Bondy, S. C. (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem. Res. Toxicol. 5, 227-231
66. Tietze, F. (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione. Applications to mammalian blood and other tissues. Anal. Biochem. 27, 502-522
67. Morrow, J. D., and Roberts, L. J. (2002) Mass spectrometric quantification of F2-isoprostanes as indicators of oxidant stress. Methods Mol. Biol. 186, 57-66
68. Birch-Machin, M. A., and Turnbull, D. M. (2001) Assaying mitochondrial respiratory complex activity in mitochondria isolated from human cells and tissues. Methods Cell Biol. 65, 97-117
69. Wu, M., Neilson, A., Swift, A. L., Moran, R., Tamagnine, J., Parslow, D., Armistead, S., Lemire, K., Orrell, J., Teich, J., Chomicz, S., and Ferrick, D. A. (2007) Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am. J. Physiol. Cell Physiol. 292, C125-C136 (Pubitemid 46115126)
70. Avadhani, N. G., Sangar, M. C., Bansal, S., and Bajpai, P. (2011) Bimodal targeting of cytochrome P450s to endoplasmic reticulum and mitochondria. The concept of chimeric signals. FEBS J. 278, 4218-4229
71. Avadhani, N. G. (2011) Targeting of the same proteins to multiple subcellular destinations. Mechanisms and physiological implications. FEBS J. 278, 4217
72. Sepuri, N. B., Yadav, S., Anandatheerthavarada, H. K., and Avadhani, N. G. (2007) Mitochondrial targeting of intact CYP2B1 and CYP2E1 and N-terminal truncated CYP1A1 proteins in Saccharomyces cerevisiae. Role of protein kinase A in the mitochondrial targeting of CYP2E1. FEBS J. 274, 4615-4630 (Pubitemid 47301721)
73. Sangar, M. C., Bansal, S., and Avadhani, N. G. (2010) Bimodal targeting of microsomal cytochrome P450s to mitochondria. Implications in drug metabolism and toxicity. Expert Opin. Drug Metab. Toxicol. 6, 1231-1251
74. Sangar, M. C., Anandatheerthavarada, H. K., Martin, M. V., Guengerich, F. P., and Avadhani, N. G. (2010) Identification of genetic variants of human cytochrome P450 2D6 with impaired mitochondrial targeting. Mol. Genet. Metab. 99, 90-97
75. Dasari, V. R., Anandatheerthavarada, H. K., Robin, M. A., Boopathi, E., Biswas, G., Fang, J. K., Nebert, D. W., and Avadhani, N. G. (2006) Role of protein kinase C-mediated protein phosphorylation in mitochondrial translocation of mouse CYP1A1, which contains a non-canonical targeting signal. J. Biol. Chem. 281, 30834-30847 (Pubitemid 44582138)
76. Dostalek, M., Brooks, J. D., Hardy, K. D., Milne, G. L., Moore, M. M., Sharma, S., Morrow, J. D., and Guengerich, F. P. (2007) In vivo oxidative damage in rats is associated with barbiturate response but not other cytochrome P450 inducers. Mol. Pharmacol. 72, 1419-1424 (Pubitemid 350146079)
77. Dostalek, M., Hardy, K. D., Milne, G. L., Morrow, J. D., Chen, C., Gonzalez, F. J., Gu, J., Ding, X., Johnson, D. A., Johnson, J. A., Martin, M. V., and Guengerich, F. P. (2008) Development of oxidative stress by cytochrome P450 induction in rodents is selective for barbiturates and related to loss of pyridine nucleotide-dependent protective systems. J. Biol. Chem. 283, 17147-17157
78. Dong, H., Dalton, T. P., Miller, M. L., Chen, Y., Uno, S., Shi, Z., Shertzer, H. G., Bansal, S., Avadhani, N. G., and Nebert, D. W. (2009) Knock-in mouse lines expressing either mitochondrial or microsomal CYP1A1. Differing responses to dietary benzo[a]pyrene as proof of principle. Mol. Pharmacol. 75, 555-567
79. Morgan, K., French, S. W., and Morgan, T. R. (2002) Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage. Hepatology 36, 122-134 (Pubitemid 34700769)
80. Uematsu, F., Ikawa, S., Kikuchi, H., Sagami, I., Kanamaru, R., Abe, T., Satoh, K., Motomiya, M., and Watanabe, M. (1994) Restriction fragment length polymorphism of the human CYP2E1 (cytochrome P450IIE1) gene and susceptibility to lung cancer. Possible relevance to low smoking exposure. Pharmacogenetics 4, 58-63 (Pubitemid 24162849)
81. Gonzalez, F. J. (2007) The 2006 Bernard B. Brodie Award Lecture. Cyp2e1. Drug Metab. Dispos. 35, 1-8
82. Novak, R. F., and Woodcroft, K. J. (2000) The alcohol-inducible form of cytochrome P450 (CYP 2E1). Role in toxicology and regulation of expression. Arch. Pharm. Res. 23, 267-282
83. Song, B.-J., Gelboin, H. V., Park, S. S., Yang, C. S., and Gonzalez, F. J. (1986) ComplementaryDNAand protein sequences of ethanol-inducible rat and human cytochrome P-450s. Transcriptional and post-transcriptional regulation of the rat enzyme. J. Biol. Chem. 261, 16689-16697 (Pubitemid 17000858)
84. Zangar, R. C., Woodcroft, K. J., Kocarek, T. A., and Novak, R. F. (1995) Xenobiotic-enhanced expression of cytochrome P450 2E1 and 2B1/2B2 in primary cultured rat hepatocytes. Drug Metab. Dispos. 23, 681-687