Abstract
The cytochrome P-450 (CYP) isoenzymes, a superfamily of heme proteins which are the terminal oxidases of the mixed function oxidases system, metabolize more than 70% of all clinically approved drugs. The highly polymorphic CYP2D6 isoform metabolizes more than 25% of most common drugs, and the phenotypes of the 70-plus allelic variants range from compromised to excessive enzymatic activity. Porphyrias are a group of inherited or acquired metabolic disorders of heme biosynthesis, due to a specific decrease in the activity of one of the enzymes of the heme pathway. Clinical signs and symptoms of porphyrias are frequently associated with exposure to precipitating agents, including clinically approved drugs. CYP enzymes, including CYP2D6, participate in the metabolism of some porphyrinogenic drugs, leading to the deregulation of heme biosynthesis. Considering that some of the drugs not recommended for use in porphyric patients are metabolized by CYP2D6, the presence of CYP2D6 polymorphisms in porphyric patients would influence the triggering of the disease when these individuals receive a precipitating agent that is metabolized by CYP2D6. To investigate CYP2D6 polymorphisms in porphyric patients, healthy Argentinean volunteers, porphyric patients, and a group of individuals with high levels of iron were studied. Results indicated that the CYP2D6*3 and CYP2D6*4 alleles, in particular, would be linked to the onset of disease. Predictive genotyping for CYP2D6 in porphyric patients holds promise as a method to improve the clinical efficacy of drug therapy and to personalize drug administration for these patients.
Highlights
The cytochrome P-450 (CYP) isoenzymes are a superfamily of heme proteins which are the terminal oxidases of the mixed-function oxidase system [1]
Our results showed a frequency of 18.6% CYP2D6*4 allele in the healthy group
The analysis of predicted phenotype distribution showed a difference in the frequency of CYP2D6*3 and CYP2D6*4 alleles between the control group and porphyric patients
Summary
The cytochrome P-450 (CYP) isoenzymes are a superfamily of heme proteins which are the terminal oxidases of the mixed-function oxidase system [1]. CYP2D6 gene is extremely polymorphic, and more than 70 allelic variants have been described [4,5]; as a result, metabolism and excretion rates of drugs vary between individuals, from extremely slow to ultra-fast. The mutant CYP2D6*3 (CYP2D6A) allele with the A2637 deletion in exon 5 and the mutant CYP2D6*4 (CYP2D6B) allele with a G1934A splice site defect are among the most common mutations. These mutations result in decreased or lack of CYP2D6 isoenzyme activity, leading to PM phenotype [7,8,9]. PM individuals have an increased risk for adverse side effects or therapeutic failure following drug treatment
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