Debrisoquine Polymorphism

Lennard MS, Tucker GT, Silas JH, et al. Debrisoquine polymorphism and the metabolism and action of metoprolol, timolol, propranolol and atenolol. Xenobiotica 1986 16 435 137. 

The debrisoquine polymorphism is now understood in terms of P450 2D6 and has been a prototype for research in this area. The characterization of the gene led to a basic understanding of the PM phenotype. The incidence of the PM phenotype is about 7% in most Northern European populations, with different phenotypic incidence (and SNPs) in other racial groups More than 70 allelic variants are now known, and 98% of the PMs in Northern European populations can be accounted for by four variant alleles . A nomenclature system has been set up for P450 alleles (using the suffixes 1, 2, 3,...) and is maintained by Oscarson at http //www.imm.ki.se/Cypalleles/. 

Two cytochrome P450 isoenzymes, CYP2D6 and CYP2C19, are involved in the metabolism of propranolol. The 4-hydroxylation of propranolol co-segregates with the debrisoquin polymorphism, but the side-chain oxidation to naphthoxylactic acid is catalysed in part by the mephenytoin isoenzyme. 

Leeman TD, Devi KP, Dayer P. Similar effect of oxidation deficiency (debrisoquine polymorphic) and quinidine on the apparent volume of distribution of ( )-metoix oloL EurJCUn Pharmacol 993) 45,65-71. 

CYP2D6 [polymorphisms] (MIM 124030) Slow metabolism of certain drugs (eg, debrisoquin), resulting in their accumulation... 

Smeraldi, E., Zanardi, R. et al. (1998). Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry, 3(6), 508-11. Wang, S. L., Huang, J. D. et al. (1993). Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects polymorphism in RFLP and DNA sequence of CYP2D6. Clin. Pharmacol. Ther., 53(4), 410-18. 

Bertilsson, L., Lou, Y. Q., Du, Y. L. et al. (1992). Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin. Pharmacol. Ther., 51, 338-97. 

Nakamura, K., Goto, F., Ray, W. A. etal. (1985). Interethnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin. Pharmacol. Ther., 10,402-8. 

Sommers de K, Moncrieff J, Avenant J. Non-correlation between debrisoquine and metoprolol polymorphisms in the Vend. Hum Toxicol 1989 8 365-368. 

Brosen K, Skjelbo E. 1991. Fluoxetine and norfluoxetine are potent inhibitors of P450IID6-the source of the sparteine/ debrisoquine oxidation polymorphism. Br J Clin Pharmacol 32 136-137. 

Dayer P, Desmeules J, Leemann T, Stribemi R. 1988. Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/ bufl). Biochem Biophys Res Commun 152 411-416. 

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. 

Relling, M.V., Evans, W.E., Fonne-Pfister, R., et al. (1989) Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes. Cancer Res. 49, 68-71. 

A variety of ethnic differences have been described in CYP2D6 function. The metabolic ratio - debrisoquine/4-hydroxydebrisoquine ratio in the urine - for a Chinese population was substantially higher than that in a Swedish comparator group - on average the Chinese are poorer metabolizers of debrisoquine than the Swedes - and there is no clear separation between normal and poor metabolizers, i.e., there do not appear to be two separate populations based on genetic polymorphism. 

Fonne-Pfister R, Meyer UA. Xenobiotic and endobiotic inhibitors of cytochrome P-450dbl function, the target of the debrisoquine/sparteine type polymorphism. Biochem Pharmacoi 1988 37 3829-3835. 

Genetic polymorphism in debrisoquin 4-hydroxylation by CYP2D6 in a Caucasian population. The semilog frequency... 

Data from Woolhouse et al Debrisoquin hydroxylation polymorphism among Ghanians and Caucasians. Clin Pharmacol Ther 1979 26 584.)... 

Figure 5.28 Compounds known to show the same oxidation polymorphism in humans as debrisoquine. The arrows indicate the site of oxidation.

Lof, A., Hansen, S.H Naslund. P, Steiner, E., Wallen, M. Hjelm, E.W. (1990a) Relationship between uptake and elimination of toluene and debrisoquin hydroxylation polymorphism. Clin. Pharmacol. Ther., 47, 412 417... 

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