Polymorphisms of CYP2D6 in control and porphyric individuals. Frequency of ultrarapid metabolizers

LAVANDERA, JIMENA; MC KEON, SOLEDAD; PARERA, VICTORIA; ROSSETTI, MARÍA VICTORIA; BATLLE, ALCIRA; BUZALEH, ANA MARIA

Estocolmo - Suecia

Congreso; PORPHYRINS AND PORPHYRIAS 2009; 2009

The Swedish Society of Medicine

CYP2D6 polymorphisms result in poor (PM), intermediate (IM), ultrarapid (UM), efficient (EM) and efficient intermediate metabolizers (EIM). Nowadays, it is known that CYP2D6 polymorphisms cause inter-individual variability in drug response influencing the treatment of several diseases. Some of CYP2D6 substrate drugs are unsafe for porphyric patients, so, polymorphisms in these individuals could influence in the triggering of the disease when they receive a precipitating agent metabolized by this isoform. Previously we investigated the presence of PM in individuals with different types of Porphyria; a lower PM frequency in porphyric patients respect to control group was observed. The aim of this work was to identify CYP2D6 UM frecuency in porphyric patients and in a control group. A total of 87 subjects, 46 healthy volunteers and 41 porphyric patients: 22 with Acute Intermittent Porphyria (AIP) and 19 with Porphyria Cutanea Tarda (PCT) were included in the study. To identify individuals carrying duplicate CYP2D6 genes, long-range PCR was used according to Steijns &  Der Weide (Clin. Chem. 44:5, 1998, 914-917) with slight modifications. PCR-RFLP.was also performed to identify CYP2D6*4 allele to avoid misclassification of subjects with *4xN nonfunctional duplication Genotype distribution of CYP2D6 alleles showed that 13% (6/46) of control group have CYP2D6 duplicated; none of these individuals presented CYP2D6*4 allele. In PCT group, 5.3% (1/19) had the CYP2D6 gene duplicated. In AIP group, 4.5% (1/22) of patients showed duplicated CYP2D6 alleles. Predicted phenotype distribution reveals that 50% of control group were classified as EM, 35% as EIM, 2.2% as PM and 13% as UM. In AIP group, 86.4% were EM, 9.1% EIM, being these results significantly different respect to control group (p<0.01) and 4.5% as UM. In PCT 63.2% were classified as EM, 26.3% as EIM, 5.3% as PM and UM. The information obtained with this research would be of impact on the practice of medicine in a near future. Some drugs have shown conflictive evidence about their porphyrinogenicity in some  individuals. So, predictive genotyping for CYP2D6 in porphyric patients could be used soon routinarily to improve the clinical efficacy of drug therapy and to personalize drug administration.