Polymorphisms of CYP2D6 in patients with porphyria cutanea tarda. Frequency of several alleles related to poor metabolizers

SORIA M; LAVANDERA J; PARERA V; ROSSETTI MV; BATLLE A; BUZALEH, ANA MARIA

Cardiff

Congreso; International Porphyrins and Porphyrias Meeting; 2011

British Association of Dermatologists

Cytochrome P4502D6 (CYP2D6) is an enzyme, predominately expressed in the liver. The gene encoding CYP2D6 is highly polymorphic; many of these variants abolish, reduce or increase CYP2D6 activity, thereby dividing individuals into poor (PM), intermediate (IM), extensive, extensive intermediate or ultrarapid metabolizers of CYP2D6-metabolized drugs. It is known that CYP2D6 polymorphisms cause interindividual variability in drug response, influencing the treatment of several diseases. Some 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 isoenzyme. Previously we investigated the presence of two alleles of CYP2D6, associated with PM phenotype, in patients with different types of porphyria such as porphyria cutanea tarda (PCT), acute intermittent porphyria (AIP) and variegate porphyria. Only in the AIP group was a significant difference with respect to healthy individuals observed. The aim of this work was to study CYP2D6 polymorphisms in PCT individuals further. For this purpose the major PM (CYP2D6*3, *4, *5, *6) and IM (CYP2D6*9, *10, *41) alleles found in caucasians were investigated. In total, 88 subjects (58 healthy volunteers and 30 PCT patients) were included in the study. The technique used involved a multiplex long-range polymerase chain reaction and a subsequent amplification refractory mutation system. In the healthy group, the genotype distribution of alleles was as follows: *3 and *6, 1Æ7% (1/58); *4, 17Æ2% (10/58); *9 and *10, 3Æ4% (2/58); *41: 13Æ8% (8/58). These findings were similar to those reported in other caucasian populations. In the PCT group, the alleles *3 and *9 were not present, while the distribution of the other alleles identified was: *4, 23Æ3% (7/30); *6 and *10, 3Æ3% (1/30); *41, 6Æ6% (2/30). Results demonstrated once again that the porphyric group showed a minor presence of polymorphisms related to PM metabolizers, reflected by the absence of CYP2D6*3 and CYP2D6*9 and the difference in the percentage of CYP2D6*41. This is the first work to analyse several CYP2D6 polymorphisms at the same time in the Argentinian population and also in individuals with porphyria.