Molecular mechanisms of genetic polymorphisms of drug metabolism

Annual Review of Pharmacology and Toxicology

Volumn 37, Issue , 1997, Pages 269-296

  Meyer, Urs A ^a   Zanger, Ulrich M ^b  

^a UNIVERSITY OF BASEL   (Switzerland)

^b DR MARGARETE FISCHER BOSCH INSTITUTE OF CLINICAL PHARMACOLOGY   (Germany)

Author keywords

CYP2C19; CYP2D6; drug metabolism; genetic polymorphism; N acetyltransferases; pharmacogenetics

Indexed keywords

ACYLTRANSFERASE; AROMATIC AMINE; DRUG METABOLIZING ENZYME; HYDRAZINE DERIVATIVE; MEPHENYTOIN;

DRUG METABOLISM; DRUG OXIDATION; GENE MUTATION; GENETIC POLYMORPHISM; HUMAN; PHARMACOGENETICS; PRIORITY JOURNAL; REVIEW;

EID: 0030995879     PISSN: 00664251     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.pharmtox.37.1.269     Document Type: Review

References (144)

1. Vogel F, Motulsky AG, eds. 1986. Human Genetics. Problems and Approaches. New York: Springer-Verlag. 435 pp.
2. Meyer UA. 1991. Genotype or phenotype: the definition of a pharmacogenetic polymorphism. Pharmacogenetics 1:66-67
3. Meyer UA, Zanger UM, Grant D, Blum M. 1990. Genetic polymorphisms of drug metabolism. In Advances in Drug Research, ed. B Testa, pp. 197-41. London: Academic
4. Kalow W. 1992. Pharmacogenetics of Drug Metabolism. New York: Pergamon
5. Meyer UA. 1992. Drugs in special patient groups: clinical importance of genetics in drug effects. In Clinical Pharmacology: Basic Principles of Therapeutics, ed. KF Melmon, HF Morelli, pp. 875-94. New York: McGraw-Hill
6. Evans DAP. 1993. Genetic Factors in Drug Therapy. Clinical and Molecular Pharmacogenetics. Cambridge: Cambridge Univ. Press
7. Meyer UA. 1994. Commentary. Pharmacogenetics: The slow, the rapid, and the ultrarapid. Proc. Natl. Acad. Sci. USA 91: 1983-84
8. Meyer UA. 1994. The molecular basis of genetic polymorphisms of drug metabolism. J. Pharm. Pharmacol. 46:409-15
9. Bertilsson L. 1995. Geographical/interracial differences in polymorphic drug oxidation. Clin. Pharmacokinet. 29:192-99
10. Daly AK. 1995. Molecular basis of polymorphic drug metabolism. J. Mol. Med. 73:539-53
11. Pacifici GM, Fracchia GN. 1995. Medicine and health. In Advances in Drug Metabolism in Man. EUR 15439. Luxembourg: Office for Official Publications of the European Communities
12. Bönicke R, Reif W. 1953. Enzymatic inactivation of isonicotinic acid hydrazide in humans and animals. Arch. Exp. Pathol. Pharmakol. 220:321-33
13. Weber WW. 1987. The Acetylator Genes and Drug Response. New York: Oxford Univ. Press
14. Evans DAP. 1989. N-Acetyltransferase. Pharmacol. Ther. 42:157-234
15. Grant DM. 1993. Molecular genetics of the N-acetyltransferases. Pharmacogenelics 3:45-50
16. Meyer UA, Blum M, Grant D, Heim M, Broly F, et al. 1993. Acetylation pharmacogenetics. In Human Drug Metabolism. From Molecular Biology to Man, ed. EH Jeffery, pp. 117-24. Boca Raton/AnnArbor/London: CRC Press
17. Vatsis KP, Weber WW. 1994. Human N-acetyltransferases. In Conjugation-Deconjugation. Reactions in Drug Metabolism and Toxicity. Handbook of Experimental Pharmacology, ed. FC Kauffmann, pp. 109-30. Berlin/Heidelberg: Springer-Verlag
18. Vatsis KP, Wendell WW, Douglas AB, Dupret J-M, Price Evans DA, et al. 1995. Nomenclature for N-acetyltransferases. Pharmacogenetics 5:1-17
19. Wolkenstein P, Carrière V, Charue D, Bastuji-Garin S, Revuz J. 1995. A slow acetylator genotype is a risk factor for sulphonamide-induced toxic epidermal necrolysis and Stevens-Johnson syndrome. Pharmacogenetics 5:255-58
20. Hayes RB, Bi W, Rothman N, Broly F, Caproaso N, et al. 1993. N-Acetylation phenotype and genotype and risk of bladder cancer in benzidine-exposed workers. Carcinogenesis 14:675-78
21. Vineis P, Bartsch H, Caporaso N, Harrington AM, Kadlubar FF, et al. 1994. Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens. Nature 369:154-56
22. Risch A, Wallace DMA, Bathers S, Sim E. 1995. Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer. Hum. Mol. Genet 4:231-36
23. Grant DM, Beer M, Blum M, Meyer UA. 1991. Monomorphic and polymorphic human arylamine N-acetyltransferases: a comparison of liver isozymes and expressed products of two cloned genes. Mol. Pharmacol. 39:184-91
24. Jenne JW. 1965. Partial purification and properties of the isoniazid transacetylase in human liver. Its relationship to the acetylation of p-aminosalicyclic acid. J. Clin. Invest. 44:1992-2002
25. Grant DM, Lottspeich F, Meyer UA. 1989. Evidence for two closely related isozymes of arylamine N-acetyl-transferase in human liver. FEBS. Lett. 244:203-7
26. Grant DM, Mörike K, Eichelbaum M, Meyer UA. 1990. Acetylation pharmacogenetics. The slow acetylator phenotype is caused by decreased or absent arylamine N-acetyltransferase in human liver. J. Clin. Invest. 85:968-72
27. Andres HH, Vogel RS, Tarr GE, Johnson L, Weber WW. 1987. Purification, physicochemical, and kinetic properties of liver acetyl-CoA: arylamine N-acetyltransferase from rapid acetylator liver. Mol. Pharmacol 31:446-56
28. Blum M, Grant DM, Demierre A, Meyer UA. 1989. N-acetylation pharmacogenetics: A gene deletion causes absence of arylamine N-acetyltransferase in liver of slow acetylator rabbits. Proc. Natl. Acad. Sci. USA 86:9554-57
29. Blum M, Grant DM, McBride W, Heim M, Meyer UA. 1990. Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol. 9:193-203
30. Ebisawa T, Deguchi T. 1991. Structure and restriction fragment length polymorphism of genes for human liver arylamine N-acetyltransferases. Biochem. Biophys. Res. Commun. 177:1252-57
31. Hickman D, Risch A, Buckle V, Spurr NK, Jeremiah SJ, et al. 1994. Chromosomal localization of human genes for arylamine N-acetyltransferase. Biochem. J. 297:441-45
32. Cribb AE, Nakamura H, Grant DM, Miller MA, Spielberg SP. 1993. Role of polymorphic and monomorphic human arylamine N-acetyltransferases in determining sulfamethoxazole metabolism. Biochem. Pharmacol. 45:1277-82
33. Minchin RF. 1995. Acetylation of p-aminobenzoylglutamate, a folic acid catabolite, by recombinant human arylamine N-acetyltransferase and U937 cells. Biochem. J. 307:1-3
34. Ward A, Summer MJ, Sim E. 1995. Purification of recombinant human N-acetyltransferase type 1 (NAT1) expressed in E. coli and characterization of its potential role in folate metabolism. Biochem. Pharmacol. 49:1759-67
35. Dupret JM, Grant DM. 1992. Site directed mutagenesis of recombinant human arylamine N-acetyltransferase expressed in E. coli: evidence for direct involvement of cys 68 in the catalytic mechanism of polymorphic human NAT2. J. Biol. Chem. 267:7381-85
36. Watanabe M, Sofuni T, Nohmi TJ. 1992. Involvement of cys69 residue in the catalytic mechanism of N-hydroxylamine O-acetyltransferase of Salmonella typhimurium: sequence similarity at the amino acid level suggests a common catalytic mechanism of acetyltransferase for S. typhimurium and higher organisms. J. Biol. Chem. 267:8427-36
37. Blum M, Demierre A, Grant DM, Heim M, Meyer UA. 1991. Molecular mechanism of slow acetylation in man. Proc. Natl. Acad. Sci. USA 88:5237-41
38. Ohsako S, Deguchi T. 1990. Cloning and expression of cDNAs for polymorphic and monomorphic arylamine N-acetyltransferases from human liver. J. Biol. Chem. 265:4630-34
39. Deguchi T. 1992. Sequences and expression of alleles of polymorphic arylamine N-acetyltransferase of human liver. J. Biol. Chem. 267:18140-47
40. Hickman D, Risch A, Camilleri JP, Sim E. 1992. Genotyping human polymorphic arylamine N-acetyltransferase: identification of new slow allotypic variants. Pharmacogenetics 2:217-26
41. Bell DA, Taylor JA, Butler MA, Stephens EA, Wiest J, et al. 1993. Gentoype/-phenotype discordance for human arylamine N-acetyltransferase (NAT2) reveals a new slow acetylator allele common in African-Americans. Carcinogenesis 14:1689-92
42. Deguchi T, Mashimo M, Suzuki T. 1990. Correlation between acetylator phenotypes and genotypes of polymorphic arylamine N-acetyltransferase in human liver. J. Biol. Chem. 265:12757-60
43. Vatsis KP, Martel KJ, Weber WW. 1991. Diverse point mutations in the human gene for polymorphic N-acetyltransferase. Proc. Natl. Acad. Sci. USA 88:6333-37
44. Cascorbi I, Drakoulis N, Brockmöller J, Maurer A, Sperling K, Roots I. 1995. Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity. Am. J. Hum. Genet. 57:581-92
45. Cascorbi I, Brockmöller J, Bauer S, Reum T, Roots I. 1996. NAT2* 12A (803A-G) codes for rapid arylamine N-acetylation in human. Pharmacogenetics 6:257-59
46. Agundez JAG, Olivera M, Martinez C, Ladero JM, Benitez J. 1996. Identification and prevalence study of 17 allelic variants of the human NAT2 gene in a white population. Pharmacogenetics 6:423-28
47. Lin HJ, Han C-Y, Lin BK, Hardy S. 1993. Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, Blacks, Hispanics and Whites: application to metabolic epidemiology. Am. J. Hum. Genet. 52:827-34
48. Lin HJ, Han C-Y, Lin BK, Hardy S. 1994. Ethnic distribution of slow acetylator mutations in the polymorphin N-acetyltransferase (NAT2) gene. Pharmacogenetics 4:125-34
49. Martinez C, Agundez JAG, Olivera M, Martin R, Ladero JM, Benitez J. 1995. Lung cancer and mutations at the polymorphic NAT2 gene locus. Pharmacogenetics 5:207-14
50. Deloménie C, Sica L, Grant DM, Krishnamoorthy R, Dupret J-M. 1996. Genotyping of the polymorphic N-acetyltransferase (NAT2*) gene locus in two native African populations. Pharmacogenetics 6:177-85
51. Abe M, Deguchi T, Suzuki T. 1993. The structure and characteristics of a fourth allele of polymorphic N-acetyltransferase gene found in the Japanese population. Biochem. Biophys. Res. Commun. 191:811-16
52. Hein DW, Ferguson RJ, Doll MA, Rustan TD, Gray K. 1994. Molecular genetics of human polymorphic N-acetyltransferase: enzymatic analysis of 15 recombinant wild-type, mutant, and chimeric NAT2 allozymes. Hum. Mol. Genet. 3:729-34
53. Cribb AE, Grant DM, Miller MA, Spielberg SP. 1991. Expression of monomorphic arylamine N-acetyltransferase (NAT1) in human leucocytes. J. Pharmacol. Exp. Ther. 259:1241-46
54. Ward A, Hickman D, Gordon JW, Sim E. 1992. Arylamine N-acetyltransferase in human red blood cells. Biochem. Pharmacol. 44:1099-104
55. Vatsis KP, Weber WW. 1993. Structural heterogeneity of Caucasian N-acetyltransferase at the NAT1 gene locus. Arch. Biochem. Biophys. 301:71-76
56. Grant DM, Vohra P, Avis Y, Ima A. 1992. Detection of a new polymorphism of human arylamine N-acetyltransferase NAT1 using p-aminosalicylic acid as an in vivo probe. Clin. Physiol. Pharmacol. 3:244
57. Arias TD, Jorge LF, Griese E-U, Inaba TEM. 1993. Polymorphic N-acetyltransferase (NAT2) in amerindian populations of Panama and Colombia: high frequencies of M3 mutation. Pharmacogenetics 3:328-31
58. Cavalli-Sforza LL, Menozzi P, Piazza A. 1994. The History and Geography of Human Genes. Princeton, NJ: Princeton Univ. Press
59. Mahgoub A, Idle JR, Dring LG, Lancester R, Smith RL. 1977. Polymorphic hydroxylation of debrisoquine in man. Lancet ii:584-86
60. Eichelbaum M, Spannbrucker N, Steincke B, Dengler JJ. 1979. Defective N-oxidation of sparteine in man: a new harmacogenetic defect. Eur. J. Clin. Pharmacol. 16:183-87
61. Alvan G, Bechtel P, Iselius L, Gundert-Remy U. 1990. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur. J. Clin. Pharmacol. 39:533-37
62. Kroemer HK, Eichelbaum M. 1995. "It's the genes, stupid." Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sci. 56:2285-98
63. Sindrup SH, Brosen K. 1995. The parmacogenetics of codeine hypoalgesia. Pharmacogenetics 5:335-46
64. Bertilsson L, Dahl ML, Sjoqvist F, Aberg Wistedt A, Humble M, et al. 1993. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 341:61
65. Brosen K, Gram LF, Sindrup S, Skjelbo E, Nielsen KK. 1992. Pharmacogenetics of tricyclic and novel antidepressants: recent developments. Clin. Neuropharmacol. 15 (suppl 1):80A-81A
66. Eichelbaum M, Gross AS. 1990. The genetic polymorphism of debrisoquine/-sparteine metabolism-clinical aspects. Pharmacol. Ther. 46:377-94
67. Meyer UA, Skoda RC, Zanger UM. 1990. The genetic polymorphism of debrisoquine/sparteine metabolism-molecular mechanisms. Pharmacol. Ther. 46:297-308
68. Gut J, Catin T, Dayer P, Kronbach T, Zanger U, Meyer UA. 1986. Debrisoquine/sparteine-type polymorphism of drug oxidation. Purification and characterization of two functionally different human liver cytochrome P-450 isozymes involved in impaired hydroxylation of the prototype substrate bufuralol. J. Biol. Chem. 261:11734-43
69. Distlerath LM, Reilly PE, Martin MV, Davis GG, Wilkinson GR, Guengerich FP. 1985. Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J. Biol. Chem. 260:9057-67
70. Dayer P, Kronbach T, Eichelbaum M, Meyer UA. 1987. Enzymatic basis of the debrisoquine/sparteine-type genetic polymorphism of drug oxidation. Characterization of bufuralol 1′-hydroxylation in liver microsomes of in vivo phenotyped carriers of the genetic deficiency. Biochem. Pharmacol. 36:4145-52
71. Zanger UM, Vilbois F, Hardwick JP, Meyer UA. 1988. Absence of hepatic cytochrome P450bufI causes genetically deficient debrisoquine oxidation in man. Biochemistry 27:5447-54
72. Gonzalez FJ, Matsunaga T, Nagata K, Meyer UA, Nebert DW, et al. 1987. Debrisoquine 4-hydroxylase: characterization of a new P450 gene subfamily, regulation, chromosomal mapping, and molecular analysis of the DA rat polymorphism. DNA 6:149-61
73. Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, et al. 1988. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331:442-46
74. Zanger UM, Meyer UA. 1989. Absent, decreased or variant P450db1 in livers with poor capacity for debrisoquine metabolism. In Cytochrome P450: Biochemistry and Biophysics, ed. I Schuster, pp. 568-71. London: Taylor & Francis
75. Zanger UM, Hauri HP, Loeper J, Homberg JC, Meyer UA. 1988. Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II. Proc. Natl. Acad. Sci. USA 85:8256-60
76. Eichelbaum M, Baur MP, Dengler HJ, Osikowska Evers BO, Tieves G, et al. 1987. Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22. Br. J. Clin. Pharmacol 23:455-58
77. Gonzalez FJ, Vilbois F, Hardwick JP, McBride OW, Nebert DW, et al. 1988. Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Genomics 2:174-79
78. Gough AC, Smith CA, Howell SM, Wolf CR, Bryant SP, Spurr NK. 1993 . Localization of the CYP2D gene locus to human chromosome 22q13.1 by polymerase chain reaction, in situ hybridization, and linkage analysis. Genomics 15:430-32
79. Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ. 1989. The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am. J. Hum. Genet. 45:889-904
80. Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer UA. 1991. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am. J. Hum. Genet. 48:943-50
81. Heim MH, Meyer UA. 1992. Evolution of a highly polymorphic human cytochrome P450 gene cluster: CYP2D6. Genomics 14:49-58
82. Hanioka N, Kimura S, Meyer UA, Gonzalez FJ. 1990. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934-A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3′ splice recognition site. Am. J. Hum. Genet. 47:994-1001
83. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman Sundberg M. 1994. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol. Pharmacol. 46:452-59
84. Skoda RC, Gonzalez FJ, Demierre A, Meyer UA. 1988. Two mutant alleles of the human cytochrome P-450db1 gene (P450C2D1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc. Natl. Acad. Sci. USA 85:5240-43
85. Evans WE, Relling MV. 1990. Xbal 16-plus 9-kilobase DNA restriction fragments identify a mutant allele for debrisoquin hydroxylase: report of a family study. Mol. Pharmacol. 37:639-42
86. Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA. 1990. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J. Biol. Chem. 265:17209-14
87. Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, et al. 1990. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 347:773-76
88. Heim M, Meyer UA. 1990. Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 336:529-32
89. Broly F, Gaedigk A, Heim M, Eichelbaum M, Morike K, Meyer UA. 1991. Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol. 10:545-58
90. Broly F, Marez D, Sabbagh N, Legrand M, Millecamps S, et al. 1995. An efficient strategy for detection of known and new mutations of the CYP2D6 gene using single strand conformation polymorphism analysis. Pharmacogenetics 5:373-84
91. Marez D, Legrand M, Sabbagh N, Lo Guidice J-M, Spire C, et al. 1996. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics. In press
92. Daly AK, Brockmöller J, Broly F, Eichelbaum M, Evans WE, Gonzalez FJ, et al. 1996. Nomenclature for human CYP2D6 alleles. Pharmacogenetics 6:193-201
93. Steen VM, Andreassen OA, Daly AK, Tefre T, Borresen AL, et al. 1995. Detection of the poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology. Pharmacogenetics 5:215-23
94. Stüven T, Griese E-U, Kroemer HK, Eichelbaum M, Zanger UM. 1996. Rapid detection of CYP2D6 null alleles by long distance- and multiplex-polymerase chain reaction. Pharmacogenetics 6:417-21
95. Evert B, Griese EU, Eichelbaum M. 1994. A missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteine. Naunyn. Schmiedebergs. Arch. Pharmacol. 350:434-39
96. 324Pro) expressed by recombinant baculovirus in insect cells. Naunyn-Schmiedeberg's Arch. Pharmacol. In press
97. Dahl ML, Johansson I, Bertilsson L, Ingelman Sundberg M, Sjoqvist F. 1995. Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J. Pharmacol. Exp. Ther. 274:516-20
98. Tyndale RF, Aoyama T, Broly F, Matsunaga T, Inaba T, et al. 1991. Identification of a new variant CYP2D6 allele lacking the codon encoding Lys 281: possible association with the poor metabolizer phenotype. Pharmacogenetics 1:26-12
99. Broly F, Meyer UA. 1993. Debrisoquine oxidation polymorphism: phenotypic consequences of a 3-base-pair deletion in exon 5 of the CYP2D6 gene. Pharmacogenetics 3:123-30
100. Agundez JA, Martinez C, Ladero JM, Ledesma MC, Ramos JM, et al. 1994. Debrisoquin oxidation genotype and susceptibility to lung cancer. Clin. Pharmacol. Ther. 55:10-14
101. Wang SL, Huang JD, Lai MD, Liu BH, Lai ML. 1993. Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: polymorphism in RFLP and DNA sequence of CYP2D6. Clin. Pharmacol. Ther. 53:410-18
102. Armstrong M, Fairbrother K, Idle JR, Daly AK. 1994. The cytochrome P450 CYP2D6 allelic variant CYP2D6J and related polymorphisms in a European population. Pharmacogenetics 4:73-81
103. Johansson I, Lundqvist E, Bertilsson L, Dahl ML, Sjoqvist F, Ingelman Sundberg M. 1993. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc. Natl. Acad. Sci. USA 90:11825-29
104. Agundez JA, Ledesma MC, Ladero JM, Benitez J. 1995. Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin. Pharmacol. Ther. 57:265-69
105. Aklillu E, Persson I, Bertilsson L, Rodriques F, Ingelman-Sundberg M. 1996. Frequent distribution of ultrarapid metabolizers of debrisoquine in a black African population carrying duplicated and multiduplicated function CYP2D6 alleles detection. J. Pharmacol. Exp. Ther. 278:441-46
106. Panserat S, Mura C, Gerard N, Vincent Viry M, Galteau MM, et al. 1994. DNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): evidence for two major allozymes in extensive metabolisers. Hum. Genet. 94:401-6
107. Masimirembwa CM, Johansson I, Hasler JA, Ingelman Sundberg M. 1993. Genetic polymorphism of cytochrome P450 CYP2D6 in Zimbabwean population. Pharmacogenetics 3:275-80
108. Jorge LF, Arias TD, Griese U, Nebert DW, Eichelbaum M. 1993. Evolutionary pharmacogenetics of CYP2D6 in Ngawbe Guaymi of Panama: allele-specific PCR detection of the CYP2D6B allele and RFLP analysis. Pharmacogenetics 3:231-38
109. Küpfer APR, Ward S, Schenker S, Preisig R, Branch RA. 1984. Stereoselective metabolism and pharmacogenetic control of 5-phenyl-5-ethylhydantoin (Nirvanol) in humans. J. Pharmacol. Exp. Ther. 230:28-33
110. Wedlund PJ, Aslanian WS, Jacqz E, McAllister CB, Branch RA, Wilkinson GR. 1985. Phenotypic differences in mephenytoin pharmacokinetis in normal subjects. J. Pharmacol. Exp. Ther. 234:662-69
111. Inaba T, Jurima M, Kalow W. 1986. Family studies of mephenytoin hydroxylation deficiency. Am. J. Hum. Genet. 38:768-72
112. Ward SA, Goto F, Nakamura K, Jacqz E, Wilkinson GR, Branch RA. 1987. S-Mephenytoin 4′-hydroxylase is inherited as an autosomal-recessive trait in Japanese families. Clin. Pharmacol. Ther. 42:96-99
113. Wilkinson GR, Guengerich FP, Branch RA. 1992. Genetic polymorphism of S-mephenytoin hydroxylation. In Pharmacogenetics of Drug Metabolism, ed. W Kalow. pp. 657-85. New York: Pergamon
114. Goldstein JA, de Morais SMF. 1994. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4:285-99
115. Küpfer A, Preisig R. 1984. Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur. J. Clin. Pharmacol. 26:753-59
116. Sohn D-R, Kusaka M, Ishizaki T, Shin S-G, Jang I-J, Chiba K. 1992. Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin. Pharmacol. Ther. 52:160-69
117. Andersson T, Regårdh C-G, Lou Y-C, Zhang Y, Dahl M-L, Bertilsson L. 1992. Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects. Pharmacogenetics. 2:25-31
118. Wright JD, Helsby NA, Ward SA. 1995. The role of S-mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalarial biguanides. Br. J. Clin. Pharmacol. 39:441-44
119. Skjelbo E, Mutabingwa TK, Bygbjerg I, Nielsen KK, Gram LG, Brosen K. 1996. Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S-mephenytoin oxidation in Tanzanians. Clin. Pharmacol. Ther. 59:304-11
120. May DG, Black CM, Olsen NJ, Csuka ME, Tanner SB, et al. 1990. Scleroderma is associated with differences in individual routes of drug metabolism. A study with dapsone, debrisoquine, and mephenytoin. Clin. Pharmacol. Ther. 48:286-95
121. Meier UT, Dayer P, Male PJ, Kronbach T, Meyer UA. 1985. Mephenytoin hydroxylation polymorphism: characterization of the enzymatic deficiency in liver microsomes of poor metabolizers phentoyped in vivo. Clin. Pharmacol. Ther. 38:488-94
122. Gut J, Meier UT, Catin T, Meyer UA. 1986. Mephenytoin-type polymorphism of drug oxidation: purification and characterization of a human liver cytochrome P-450 isozyme catalyzing microsomal mephenytoin hydroxylation. Biochem. Biophys. Acta 884:435-47
123. Shimada T, Misono KS, Guengerich FP. 1986. Human liver microsome cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism: purification and characterization ot two similar forms involved in the reaction. J. Biol. Chem. 261:909-21
124. Ged C, Umbenhauer DR, Bellew TM, Bork RW, Srivastave P, et al. 1994. Characterization of cDNAs, mRNAs, and proteins related to human liver microsomal cytochrome P-450 (S)-mephenytoin 4′-hydroxylase. Biochemistry 27:6929-40
125. Meier UT, Meyer UA. 1987. Genetic polymorphism of human cytochrome P450 S-mephenytoin-4-hydroxylase. Biochemistry 26:8466-74
126. Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA. 1991. Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. Biochemistry 30:3247-55
127. Wrighton SA, Stevens JC, Becker GW, VandenBranden M. 1993. Isolation and characterization of human liver cytochrome P4502C19: correlation between 2C19 and S-mephenytoin 4′-hydroxylation. Arch. Biochem. Biophys. 306:240-45
128. Goldstein JA, Faletto MB, Romkes-Sparks M, Sullivan T, Raucy JL, et al. 1994. Evidence for a role for 2C19 in metabolism of S-mephenytoin in humans. Biochemistry 33:1743-52
129. de Morais SMF, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. 1994. The major defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J. Biol. Chem. 269:15419-22
130. Meehan RR, Gosden JR, Rout D, Hastle ND, Friedberg T. 1988. Human cytochrome P-450 PB-1: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am. J. Hum. Genet. 42:26-37
131. de Morais SMF, Schweikl H, Blaisdell J, Goldstein JA. 1993. Gene structure and upstream regulatory regions of human CYP2C9 and CYP2C18. Biochem. Biophys. Res. Commun. 194:194-201
132. de Morais SMF, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA. 1994. Identification of a new genetic defect responsible for the polymorphism of S-mephenytoin metabolism in Japanese. Mol. Pharmacol. 46:594-98
133. Brosen K, de Morais SMF, Meyer UA, Goldstein JA. 1995. A multifamily study on the relationship between CYP2C19 genotype and S-mephenytoin oxidation phenotype. Pharmacogenetics 5:312-17
134. Evans DAP, Krahn P, Narayanan N. 1995. The mephenytoin (cytochrome P450 2C 19) and dextromethorphan (cytochrome P450 2D6) polymorphisms in Saudi Arabians and Filipinos. Pharmacogenetics 5:64-71
135. Mikus G, Bochner F, Eichelbaum M, Horak P, Somogyi AA, Spector S. 1994. Endogenous codeine and morphine in poor and extensive metabolisers of the CYP2D6 (Debrisoquine/Sparteine) polymorphism. J. Pharmacol. Exp. Ther. 268: 546-51
136. Yokota H, Tamura S, Furuya H, Kimura S, Watanabe M, et al. 1993. Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism. Pharmacogenetics 3:256-63
137. Broly F, Marez D, Lo Guidice JM, Sabbagh N, Legrand M, et al. 1995. A nonsense mutation in the cytochrome P450 CYP2D6 gene identified in a Caucasian with an enzyme deficiency. Hum. Genet. 96:601-3
138. Brosen K, Nielsen PN, Brusgaard K, Gram LF, Skjodt K. 1994. CYP2D6 geno-type determination in the Danish population. Eur. J. Clin. Pharmacol. 47:221-25
139. Dahl ML, Yue QY, Roh HK, Johansson I, Sawe J, et al. 1995. Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects. Pharmacogenetics 5:159-64
140. 341/803) and wild-type human polymorphic N-acetyltransferase (NAT2) alleles. Drug Metab. Disp. 22:371-376
141. Marez D, Sabbagh N, Legrand M, Lo Guidice JM, Boone P, Broly F. 1995. A novel CYP2D6 allele with an abolished splice recognition site associated with the poor metabolizer phenotype. Pharmacogenetics 5:305-11
142. Ilett KF, Chiswell GM, Spargo RM, Platt E, Minchin RF. 1993. Acetylation phenotype and genotype in Aboriginal leprosy patients from the north-west region of Western Australia. Pharmacogenetics 3:264-69
143. Saxena R, Shaw GL, Relling MV, Frame JN, Moir DT, et al. 1994. Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype. Hum. Mol. Genet. 3:923-26
144. Weerasuriya K, Jayakody RL, Smith CA, Wolf CR, Tucker GT, Lennard S. 1994. Debrisoquine and mephenytoin oxidation in Sinhalese: a population study. Br. J. Clin.Pharmacol. 38:466-70