Poor Metabolizer Phenotype

Poor Metabolizer Phenotype Population Pharmacokinetics Positron Emission Tomography Post-translational Modification Potassium Channels Potassium Competitive Acid Blockers PP... 

Goldstein, J. A., Ishizaki, T. etal. (1997). Frequencies ofthe defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics, 7(1), 59-64. 

Ibeanu GC, Blaisdell ], Ferguson R], Ghanayem Bl, Brosen K, Benhamou S et al. A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-me-phenytoin. J Pharmacol Exp Ther 1999 290[2] 635—640. 

Ibeanu, G. C., BlaisdeU, J., Ghanayem, B. 1., et al. (1998) An additional defective allele, CYP2C19 5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics. 8, 129-135. 

Figure 5.27 The plasma concentration of debrisoquine after a single oral dose (10 mg) in human subjects of the extensive (o) and poor ( ) metabolizer phenotypes. Source From Ref. 32.

The biochemical basis for the trait is an almost complete absence of one form of cytochrome P-450, CYP2D6. It seems that there are several mutations, which give rise to the poor metabolizer phenotype. These mutations produce incorrectly spliced, variant mRNAs in the liver from poor metabolizers. At least three mutant alleles have been described for the CYP2D6 gene and in those with "poor metabolizer" status. A large number of mutations have also been described some of which, but not all, affect enzyme activity. However, for some of... 

G. Ibeanu, J. Blaisdell, B.I. Ghanayem, C. Beyeler, S. Benhamou, C. Bouchardy, G.R. Wilkinson, P. Dayer, A.K. Daly, J.A. Goldstein, An Additional Defective Allele, CYP2C19 5, Contributes to the S -Mephenytoin Poor Metabolizer Phenotype in Caucasians , Pharmacogenetics, 8,129-135 (1998). 

TPMT) or the liver (for UGT and CYP2C9). Certain mutations in these isoforms, or gene variants, produce different phenotypes but most important to drug dosing is the poor metabolizer phenotype that results in heightened exposure to either the parent drug or a major metabolite, or reduced exposure to an active metabolite (e.g., morphine from codeine administration). 

Nunoya K, Yokoi T, Takahashi Y, Kimura K, Kinoshita M, Kamataki T. Homologous unequal crossover within the human CYP2A gene cluster as a mechanism for the deletion of the entire CYP2A6 gene associated with the poor metabolizer phenotype. J Biochem (Tokyo) 1999 126(2) 402-407. 

Relling MV, Cherrie J, Schell MJ, et al. Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American black versus white subjects. Clin Pharmacol Ther 1991 50 308-313. 

These data show that there can be great complexity even if we deal with a single variable gene as in traditional pharmacogenetics. It is a relatively simple process to count the absence of enzyme activity ( the poor metabolizer phenotype ) in one population, but data thus obtained, for instance, in Europe, may be useless everywhere else. 

Polymorphisms also exist for specific isoenzymes of cytochrome P450. For example, there is a polymorphism within the human population for a cytochrome P450 isoenzyme that catalyzes the 4-hyroxylation of the drug debrisoquine. Extensive metabolizers hydroxylate this drug 10-200 times faster than poor metabolizers . Poor metabolizers express much less of the isoenzyme involved in this reaction than extensive metabolizers. This polymorphism also appears to affect the metabolism of environmental agents. For example, there appears to be an association between the poor-metabolizer phenotype and Parkinson s disease. By contrast, the extensive-metabolizer phenotype may be correlated with an increased risk of developing cancer. 

Finally, specific interactions between the target enzyme or protein and other drugs, chemicals, or some foods can change the phenotype, such as by converting a normal or extensive metabolizer phenotype to a poor metabolizer phenotype. For example, grapefruit juice has been shown to inhibit and many antidepressant medica-... 

The biochemical basis for the trait is an almost complete absence of one form of cytochrome P-450, CYP 2D6. It seems that there are several mutations which give rise to the poor metabolizer phenotype. These... 

In addition to an efficient-metabolism phenotype, variant alleles encode a poor-metabolism phenotype, with low or no enzyme activity towards a particular drug. On occasion, because of one or more gene dupH-cations, a variant genotype might involve a very high ultra-metabolism phenotype resulting in treatment failure and toxic effects. Similarly, rates of detoxification and sometimes of metabolic activation of environmental chemicals can be strikingly different between individuals with different CYP haplotypes. Of particular... 

Tyndale, R., T. Aoyama, F. Broly, T. Matsunaga, T. Inaba, W. Kalow 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, 26-32. 

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