Title : CYP2D6 gene polymorphisms and Renal Disease
Abstract:
The CYP2D6 gene (22q13.2) encodes the CYP2D6 protein that localises to the endoplasmic reticulum, and is highly expressed in liver, brain, intestinal tissue and lymphoid cells; it comprises only 2–4% part of total hepatic CYP content but is a main drug-metabolising enzyme responsible for metabolism of ~ 20% of commonly used drugs comprising varied substrates including analgesics, antidepressants, antihypertensives and the anti-cancer agent, tamoxifen. CYP2D6 is highly polymorphic and its genetic complexity contributes to its functional variation with rate of CYP2D6-mediated microsomal metabolism varying least by 60-fold between individuals. Chronic kidney disease can also affect non-renal clearance mechanisms such as hepatic and intestinal cytochrome P450 (CYP) enzymes and drug transport protein while the reduced activity of CYP isoforms can affect the metabolism of many medications preventing optimal patient outcomes and may be genotoxic as well. There may be drug toxicity from medications that are not adequately removed by dialysis compounding problems and mortality related to polypharmacy. Also depending on the genotype of CYP2D6 given its highly polymorphic nature, the inter-individual variation in CYP2D6 activity can have significant clinical consequences, being absent or be increased up to 18–20times. This can have implications for pro-drug activation/inactivation, and of the effects of biotransformation on the prescription of drug-types and dose-levels, hence there is a need to discern the drug-detoxifying and metabolic genotypes/phenotypes. CYP2D6 gene polymorphisms can result in four classes of metabolic phenotypes viz. ultrarapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers, based upon allelic combinations.
Therefore, it was thought prudent to genotype some single nucleotide polymorphisms (SNPs) of CYP2D6 *2,*4,*10 in kidney patients and healthy controls. Among the three CYP2D6*2,*4,*10 alleles genotyped in patients and controls and considered singly, *2 allele has enzymatic activity like that of wild type and the metabolizer status is EM, *4 allele causes a splicing defect and so enzyme is inactive and metabolizer status is PM, *10 allele causes an amino acid substitution with the result that the enzyme is unstable and metabolizer status is IM. On the basis of CYP2D6*2 genotypes, all patients and controls were phenotypically extensive metabolizers (gEM). Based upon CYP2D6*4 genotypes, 53.50% patients and 62.86% controls were extensive metabolizers (gEM) and 7.00% patients vs. 2.86% controls were poor metabolizers (gPM). For the CYP2D6*10 allele, all the patients and controls were extensive metabolizers (gEM) with lack of the intermediate metabolizing phenotype in the absence of the variant genotype.
