Impact of rat P450 genetic polymorphism on diazepam metabolism

Expert Opinion on Drug Metabolism and Toxicology

Volumn 5, Issue 11, 2009, Pages 1421-1433

  Sakai, Noriaki ^a   Ishizuka, Mayumi ^a  

^a HOKKAIDO UNIVERSITY   (Japan)

Author keywords

Cytochrome P450 2D; Debrisoquine; Diazepam; Drug metabolism; Genetic polymorphism; Interstrain differences; Intrastrain differences; Mephenytoin; Rat

Indexed keywords

4 HYDROXY N DESMETHYLDIAZEPAM; 4 HYDROXYDIAZEPAM; CYTOCHROME P450; CYTOCHROME P450 2B6; CYTOCHROME P450 2C11; CYTOCHROME P450 2C19; CYTOCHROME P450 2D; CYTOCHROME P450 2D1; CYTOCHROME P450 2D2; CYTOCHROME P450 2D3; CYTOCHROME P450 2D4; CYTOCHROME P450 2D6; CYTOCHROME P450 3A; CYTOCHROME P450 3A2; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; DEBRISOQUINE; DIAZEPAM; DRUG METABOLITE; NORDAZEPAM; OXAZEPAM; RIFAMPICIN; TEMAZEPAM; UNCLASSIFIED DRUG;

ANXIETY DISORDER; CATALYSIS; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG EXCRETION; DRUG METABOLISM; DRUG POTENTIATION; DRUG PROTEIN BINDING; GENETIC POLYMORPHISM; GENETIC TOXICOLOGY; GENETIC VARIABILITY; GENOTYPE PHENOTYPE CORRELATION; HUMAN; INSOMNIA; NONHUMAN; PHARMACODYNAMICS; RAT STRAIN; REVIEW; SEIZURE; SINGLE DRUG DOSE; SPECIES DIFFERENCE; STRAIN DIFFERENCE; WISTAR RAT;

ANIMALS; CYTOCHROME P-450 ENZYME SYSTEM; DIAZEPAM; HUMANS; HYDROXYLATION; HYPNOTICS AND SEDATIVES; POLYMORPHISM, GENETIC; RATS; SPECIES SPECIFICITY;

ANIMALIA; RATTUS;

EID: 70449097665     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425250903207002     Document Type: Review

References (97)

1. Sachidanandam R, Weissman D, Schmidt SC, et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001;409:928-933
2. Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet 2002;360(9340):1155-1162
3. Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 2001;52(4):349-355
4. Cascorbi I. Pharmacogenetics of cytochrome p4502D6: genetic background and clinical implication. Eur J Clin Invest 2003;33(Suppl 2):17-22
5. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005;5(1):6-13
6. Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004;369(1):23-37
7. Gonzalez FJ, Vilbois F, Hardwick JP, et al. Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Genomics 1988;2(2):174-179
8. Available from: http://www.imm.ki.se/ CYPalleles/cyp2d6.htm 9. Gonzalez FJ, Matsunaga T, Nagata K, et al. Debrisoquine 4-hydroxylase: characterization of a new P450 gene subfamily, regulation, chromosomal mapping, and molecular analysis of the DA rat polymorphism. DNA 1987;6(2):149-161
9. Boobis AR, Seddon CE, Davies DS. Bufuralol 1-hydroxylase activity of the rat. Strain differences and the effects of inhibitors. Biochem Pharmacol 1986;35(17):2961-2965
10. Yamamoto Y, Tasaki T, Nakamura A, et al. Molecular basis of the Dark Agouti rat drug oxidation polymorphism: importance of CYP2D1 and CYP2D2. Pharmacogenetics 1998;8(1):73-82
11. Colado MI, Williams JL, Green AR. The hyperthermic and neurotoxic effects of 'Ecstasy' (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype. Br J Pharmacol 1995;115(7):1281-1289
12. Stresser DM, Turner SD, Blanchard AP, et al. Cytochrome P450 fluorometric substrates: identification of isoform-selective probes for rat CYP2D2 and human CYP3A4. Drug Metab Dispos 2002;30(7):845-852
13. Guentert TW. Pharmacokinetics of benzodiazepines and of their metabolites. Prog Drug Metab 1984;8:241-386
14. Klotz U, Antonin KH, Bieck PR. Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig and rat. J Pharmacol Exp Ther 1976;199(1):67-73
15. Eatman FB, Colburn WA, Boxenbaum HG, et al. Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects. J Pharmacokinet Biopharm 1977;5(5):481-494
16. Seddon T, Michelle I, Chenery RJ. Comparative drug metabolism of diazepam in hepatocytes isolated from man, rat, monkey and dog. Biochem Pharmacol 1989;38(10):1657-1665
17. Fujita S, Chiba M, Ohta M, et al. Alteration of plasma sex hormone levels associated with old age and its effect on hepatic drug metabolism in rats. J Pharmacol Exp Ther 1990;253(1):369-374
18. Greenblatt DJ, Harmatz JS, Shader RI. Factors influencing diazepam pharmacokinetics: age, sex, and liver disease. Int J Clin Pharmacol Biopharm 1978;16(4):177-179
19. Ohnhaus EE, Park BK, Colombo JP, et al. The effect of enzyme induction on diazepam metabolism in man. Br J Clin Pharmacol 1979;8(6):557-563
20. Ohnhaus EE, Brockmeyer N, Dylewicz P, et al. The effect of antipyrine and rifampin on the metabolism of diazepam. Clin Pharmacol Ther 1987;42(2):148-156
21. Klotz U, Reimann I. Delayed clearance of diazepam due to cimetidine. N Engl J Med 1980;302(18):1012-1014
22. Bertilsson L, Henthorn TK, Sanz E, et al. Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype. Clin Pharmacol Ther 1989;45(4):348-355
23. Boxenbaum H. Comparative pharmacokinetics of benzodiazepines in dog and man. J Pharmacokinet Biopharm 1982;10(4):411-426
24. Jack ML, Colburn WA. Pharmacokinetic model for diazepam and its major metabolite desmethyldiazepam following diazepam administration. J Pharm Sci 1983;72(11):1318-1323
25. Bertilsson L, Baillie TA, Reviriego J. Factors influencing the metabolism of diazepam. Pharmacol Ther 1990;45(1):85-91
26. Kanto J, Sellman R, Haataja M, et al. Plasma and urine concentrations of diazepam and its metabolites in children, adults and in diazepam-intoxicated patients. Int J Clin Pharmacol Biopharm 1978;16(6):258-264
27. Yasumori T, Nagata K, Yang SK, et al. Cytochrome P450 mediated metabolism of diazepam in human and rat: involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner. Pharmacogenetics 1993;3(6):291-301
28. Andersson T, Miners JO, Veronese ME, et al. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin Pharmacol 1994;38(2):131-137
29. Jung F, Richardson TH, Raucy JL, et al. Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases. Drug Metab Dispos 1997;25(2):133-139
30. Yang TJ, Shou M, Korzekwa KR, et al. Role of cDNA-expressed human cytochromes P450 in the metabolism of diazepam. Biochem Pharmacol 1998;55(6):889-896
31. Wrighton SA, Stevens JC, Becker GW, et al. Isolation and characterization of human liver cytochrome P450 2C19: correlation between 2C19 and S-mephenytoin 4-hydroxylation. Arch Biochem Biophys 1993;306(1):240-245
32. Goldstein JA, Faletto MB, Romkes-Sparks M, et al. Evidence that CYP2C19 is the major (S)-mephenytoin 4-hydroxylase in humans. Biochemistry 1994;33(7):1743-1752
33. Yang TJ, Krausz KW, Sai Y, et al. Eight inhibitory monoclonal antibodies define the role of individual P-450s in human liver microsomal diazepam, 7-ethoxycoumarin, and imipramine metabolism. Drug Metab Dispos 1999;27(1):102-109
34. McManus ME, Burgess WM, Veronese ME, et al. Metabolism of 2-acetylaminofluorene and benzo(a)pyrene and activation of food-derived heterocyclic amine mutagens by human cytochromes P-450. Cancer Res 1990;50(11):3367-3376
35. Chenery RJ, Ayrton A, Oldham HG, et al. Diazepam metabolism in cultured hepatocytes from rat, rabbit, dog, guinea pig, and man. Drug Metab Dispos 1987;15(3):312-317
36. Andrews SM, Griffiths LA. The metabolism and disposition of [2-14C] diazepam in the streptozotocin-diabetic rat. Xenobiotica 1984;14(10):751-760
37. Zomorodi K, Carlile DJ, Houston JB. Kinetics of diazepam metabolism in rat hepatic microsomes and hepatocytes and their use in predicting in vivo hepatic clearance. Xenobiotica 1995;25(9):907-916
38. Saito K, Kim HS, Sakai N, et al. Polymorphism in diazepam metabolism in Wistar rats. J Pharm Sci 2004;93(5):1271-1278
39. Saito K, Sakai N, Kim HS, et al. Strain differences in diazepam metabolism at its three metabolic sites in sprague-dawley, brown norway, dark agouti, and wistar strain rats. Drug Metab Dispos 2004;32(9):959-965
40. Jauregui HO, Ng SF, Gann KL, et al. Xenobiotic induction of P-450 PB-4 (IIB1) and P-450c (IA1) and associated monooxygenase activities in primary cultures of adult rat hepatocytes. Xenobiotica 1991;21(9):1091-1106
41. Reilly PE, Thompson DA, Mason SR, et al. Cytochrome P450IIIA enzymes in rat liver microsomes: involvement in C3-hydroxylation of diazepam and nordazepam but not N-dealkylation of diazepam and temazepam. Mol Pharmacol 1990;37(5):767-774
42. Neville CF, Ninomiya S, Shimada N, et al. Characterization of specific cytochrome P450 enzymes responsible for the metabolism of diazepam in hepatic microsomes of adult male rats. Biochem Pharmacol 1993;45(1):59-65
43. Waxman DJ. Rat hepatic cytochrome P-450 isoenzyme 2c. Identification as a male-specific, developmentally induced steroid 16 alpha-hydroxylase and comparison to a female-specific cytochrome P-450 isoenzyme. J Biol Chem 1984;259(24):15481-15490
44. Gonzalez FJ, Song BJ, Hardwick JP. Pregnenolone 16 alpha-carbonitrile- inducible P-450 gene family: gene conversion and differential regulation. Mol Cell Biol 1986;6(8):2969-2976
45. Chow T, Imaoka S, Hiroi T, et al. Developmental changes in the catalytic activity and expression of CYP2D isoforms in the rat liver. Drug Metab Dispos 1999;27(2):188-192
46. Sakai N, Saito K, Kim HS, et al. Importance of CYP2D3 in polymorphism of diazepam p-hydroxylation in rats. Drug Metab Dispos 2005;33(11):1657-1660
47. Matsunaga E, Gonzalez FJ. Specific cytosine demethylations within the first exons of the rat CYP2D3 and CYP2D5 genes are associated with activation of hepatic gene expression during development. DNA Cell Biol 1990;9(6):443-452
48. Matsunaga E, Zanger UM, Hardwick JP, et al. The CYP2D gene subfamily: analysis of the molecular basis of the debrisoquine 4-hydroxylase deficiency in DA rats. Biochemistry 1989;28(18):7349-7355
49. St-Pierre MV, Pang KS. Concentration-dependent metabolism of diazepam in mouse liver. J Pharmacokinet Biopharm 1995;23(3):243-266
50. Schwartz MA, Koechlin BA, Postma E, et al. Metabolism of diazepam in rat, dog, and man. J Pharmacol Exp Ther 1965;149(3):423-435
51. Coutinho CB, Cheripko JA, Carbone JJ, et al. Behavioural changes in primates and diazepam metabolism. Xenobiotica 1973;3(10):681-690
52. Seddon T, Lockwood GF, Chenery RJ. In vitro drug metabolism and pharmacokinetics of diazepam in cynomolgus monkey hepatocytes during culture for six days. Biochem Pharmacol 1989;38(16):2621-2630
53. Jommi G, Manitto P, Silanos MA. Metabolism of diazepam in rabbits. Arch Biochem Biophys 1964;108:562-568
54. Inaba T, Tait A, Nakano M, et al. Metabolism of diazepam in vitro by human liver. Independent variability of N-demethylation and C3-hydroxylation. Drug Metab Dispos 1988;16(4):605-608
55. Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet 1995;29(3):192-209
56. Sohn DR, Kusaka M, Ishizaki T, et al. Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin Pharmacol Ther 1992;52(2):160-169
57. Andersson T, Regardh CG, Dahl-Puustinen ML, et al. Slow omeprazole metabolizers are also poor S-mephenytoin hydroxylators. Ther Drug Monit 1990;12(4):415-416
58. Zhang YA, Reviriego J, Lou YQ, et al. Diazepam metabolism in native Chinese poor and extensive hydroxylators of S-mephenytoin: interethnic differences in comparison with white subjects. Clin Pharmacol Ther 1990;48(5):496-502
59. Bertilsson L, Kalow W. Why are diazepam metabolism and polymorphic S-mephenytoin hydroxylation associated with each other in white and Korean populations but not in Chinese populations? Clin Pharmacol Ther 1993;53(5):608-610
60. Qin XP, Xie HG, Wang W, et al. Effect of the gene dosage of CgammaP2C19 on diazepam metabolism in Chinese subjects. Clin Pharmacol Ther 1999;66(6):642-646
61. Wan J, Xia H, He N, et al. The elimination of diazepam in Chinese subjects is dependent on the mephenytoin oxidation phenotype. Br J Clin Pharmacol 1996;42(4):471-474
62. Ghoneim MM, Korttila K, Chiang CK, et al. Diazepam effects and kinetics in Caucasians and Orientals. Clin Pharmacol Ther 1981;29(6):749-756 (Pubitemid 11006722)
63. Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002;41(12):913-958
64. Inomata S, Nagashima A, Itagaki F, et al. CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia. Clin Pharmacol Ther 2005;78(6):647-655
65. Gallaher EJ, Hollister LE, Gionet SE, et al. Mouse lines selected for genetic differences in diazepam sensitivity. Psychopharmacology (Berl) 1987;93(1):25-30
66. Wilks L, File SE, Martin IL. Evidence of strain differences in GABA-benzodiazepine coupling. Psychopharmacology (Berl) 1987;93(1):127-132
67. Griebel G, Belzung C, Perrault G, et al. Differences in anxiety-related behaviours and in sensitivity to diazepam in inbred and outbred strains of mice. Psychopharmacology (Berl) 2000;148(2):164-170
68. Robertson HA, Martin IL, Candy JM. Differences in benzodiazepine receptor binding in Maudsley reactive and Maudsley non-reactive rats. Eur J Pharmacol 1978;50(4):455-457
69. Shephard RA, Nielsen EB, Broadhurst PL. Sex and strain differences in benzodiazepine receptor binding in Roman rat strains. Eur J Pharmacol 1982;77(4):327-330
70. Van der Laan JW, de Boer SF, Van der Gugten J, et al. Differences in the duration of sedative and anxiolytic effects of desmethyldiazepam in two outbred Wistar strains. Pharmacol Biochem Behav 1991;39(1):149-153
71. Van der Laan JW, de Groot G, Wortelboer H, et al. Pharmacokinetic differences of desmethyldiazepam in three outbred Wistar strains related to differences in liver enzyme activities. Pharmacol Toxicol 1993;73(4):229-232
72. Bert B, Fink H, Sohr R, et al. Different effects of diazepam in Fischer rats and two stocks of Wistar rats in tests of anxiety. Pharmacol Biochem Behav 2001;70(2-3):411-420
73. Hogg S. A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav 1996;54(1):21-30
74. Ramos A, Berton O, Mormede P, et al. A multiple-test study of anxiety-related behaviours in six inbred rat strains. Behav Brain Res 1997;85(1):57-69
75. Mechan AO, Moran PM, Elliott M, et al. A comparison between Dark Agouti and Sprague-Dawley rats in their behaviour on the elevated plus-maze, open-field apparatus and activity meters, and their response to diazepam. Psychopharmacology (Berl) 2002;159(2):188-195
76. Al-Dabbagh SG, Idle JR, Smith RL. Animal modelling of human polymorphic drug oxidation-the metabolism of debrisoquine and phenacetin in rat inbred strains. J Pharm Pharmacol 1981;33(3):161-164
77. Schulz-Utermoehl T, Bennett AJ, Ellis SW, et al. Polymorphic debrisoquine 4-hydroxylase activity in the rat is due to differences in CYP2D2 expression. Pharmacogenetics 1999;9(3):357-366
78. Pellow S, Chopin P, File SE, et al. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985;14(3):149-167
79. File SE, Zangrossi H Jr. "One-trial tolerance" to the anxiolytic actions of benzodiazepines in the elevated plus-maze, or the development of a phobic state? Psychopharmacology (Berl) 1993;110(1-2):240-244
80. Morita K, Maeda Y, Masuda M, et al. Strain differences in CYP3A-mediated C-8 hydroxylation (1,3,7-trimethyluric acid formation) of caffeine in Wistar and Dark Agouti rats. Rapid metabolism of caffeine in debrisoquine poor metabolizer model rats. Biochem Pharmacol 1998;55(9):1405-1411
81. Lopez-Rubalcava C. Pre- or postsynaptic activity of 5-HT1A compounds in mice depends on the anxiety paradigm. Pharmacol Biochem Behav 1996;54(4):677-686
82. Liebsch G, Linthorst AC, Neumann ID, et al. Behavioral, physiological, and neuroendocrine stress responses and differential sensitivity to diazepam in two Wistar rat lines selectively bred for high- and low-anxiety-related behavior. Neuropsychopharmacology 1998;19(5):381-396
83. Wan J, Imaoka S, Chow T, et al. Expression of four rat CYP2D isoforms in Saccharomyces cerevisiae and their catalytic specificity. Arch Biochem Biophys 1997;348(2):383-390
84. Masubuchi Y, Umeda S, Chiba M, et al. Selective 3-hydroxylation deficiency of lidocaine and its metabolite in Dark Agouti rats. Biochem Pharmacol 1991;42(3):693-695
85. Masubuchi Y, Umeda S, Igarashi S, et al. Participation of the CYP2D subfamily in lidocaine 3-hydroxylation and formation of a reactive metabolite covalently bound to liver microsomal protein in rats. Biochem Pharmacol 1993;46(10):1867-1869
86. Carcillo JA, Parise RA, Adedoyin A, et al. CYP2D6 mRNA expression in circulating peripheral blood mononuclear cells correlates with in vivo debrisoquine hydroxylase activity in extensive metabolizers. Res Commun Mol Pathol Pharmacol 1996;91(2):149-159
87. Romkes-Sparks M, Mnuskin A, Chern HD, et al. Correlation of polymorphic expression of CYP2D6 mRNA in bladder mucosa and tumor tissue to in vivo debrisoquine hydroxylase activity. Carcinogenesis 1994;15(9):1955-1961
88. Sakai N, Saito K, Sakamoto KQ, et al. Genetic basis of inter- and intrastrain differences in diazepam p-hydroxylation in rats. Drug Metab Dispos 2009;37(2):268-271
89. Maquat LE. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 2004;5(2):89-99
90. Endrizzi K, Fischer J, Klein K, et al. Discriminative quantification of cytochrome P4502D6 and 2D7/8 pseudogene expression by TaqMan real-time reverse transcriptase polymerase chain reaction. Anal Biochem 2002;300(2):121-131
91. Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002;3(2):229-243
92. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27(4):383-391
93. Busi F, Cresteil T. CYP3A5 mRNA degradation by nonsense-mediated mRNA decay. Mol Pharmacol 2005;68(3):808-815
94. Okamoto K, Yamori Y, Ooshima A, et al. Establishment of the inbred strain of the spontaneously hypertensive rat and genetic factors involved in hypertension. In spontaneous hypertension: its pathogenesis and complicatioins: Tokyo: Igaku Shoin, 1972. p. 1-8
95. Landgraf R, Wigger A. High vs low anxiety-related behavior rats: an animal model of extremes in trait anxiety. Behav Genet 2002;32(5):301-314
96. Muller JR, Le KM, Haines WR, et al. Hemodynamic response pattern predicts susceptibility to stress-induced elevation in arterial pressure in the rat. Am J Physiol Regul Integr Comp Physiol 2001;281(1):R31-7
97. Fedrowitz M, Kamino K, Loscher W. Significant differences in the effects of magnetic field exposure on 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in two substrains of Sprague-Dawley rats. Cancer Res 2004;64(1):243-251