Genetic polymorphism of xenobiotic metabolising enzymes : implications for interindividual and interethnic differences in drug metabolism and cancer susceptibility

Abstract

Genetic factors are of importance for interindividual and interethnic differences in drug response and cancer susceptibility. In the present investigation the role of genetic polymorphism in the cytochromes P450 CYPIAI, CYP2C19, CYP2D6, CYP2EI as well as in glutathione S-transferase Ml (GSTMI) and microsomal epoxide hydrolase (mEH) for differences in drug response and cancer susceptibility has been investigated in various ethnic populations. The polymorphism of debrisoquine hydroxylase (CYP2D6) and S-mephenytoin hydroxylase (CYP2CI9) has been well documented in Caucasian and Oriental populations but not in African populations.

Examination of an Ethiopian population revealed an unexpectedly high amount of subjects (29%) with duplicated and multi-duplicated active CYP2D6 genes (n=l 15), whereas only two poor metabolizers (PMs) of debrisoquine were found. About 5% of the Ethiopian population were poor metabolizers of S-mephenytoin and the two known mutant alleles CYP2C19*2 and CYP2C19*3 explained all the PMs. Diminished CYP2D6 activity has also been observed in a Zimbabwean Shona population (ZimS). CYP2D6 genes were sequenced from ZimS subjects being slow, intermediate and fast in debrisoquine hydroxylation. A new variant gene (CYP2D6*17) exhibiting three functional mutations (Thrl07-11e, Arg296-Cys, Ser486-Thr)-was found. The allele frequency in the ZimS population was 34% and showed a gene dose association with lower capacity for debrisoquine hydroxylation.

The distribution of the CYP2D6*17 allele m the Ethiopian population with an allele frequency of 9% partially explained the lower debrisoquine hydroxylase activity observed in this population. A Japanese study described a lower frequency of a variant CYP2EI allele (C) in lung cancer patients as compared to controls. Such a relationship was not found when the CYP2EI polymorphism was examined in Swedish lung cancer patients (n=193) and controls (n=206). By contrast, a significantly lower frequency of another allele (c2), described to influence CYP2EI gene expression in vitro, was found in the lung cancer patients. A similar tendency was also found when Chinese lung cancer patients and a reference population was compared, whereas no differences were seen in the distribution of polymorphic alleles of CYPIAI and GSTMI, in contrast to studies previously carried out among Japanese.

The distribution of polymorphic mEH alleles were found to be similar in the reference and lung cancer groups. A polymorphism in the CYPIAI gene causing an lle462-Val amino acid exchange has been found. CYPlAI-Val has been claimed to be overrepresented among lung cancer patients and to cause a higher activity and formation of mutagens from benzo(a)pyrene as compared to CYPlAI-lle. Construction of the corresponding cDNAs and expression in yeast revealed, however, that they exhibited the same kinetics for benzo(a)pyrene and ethoxyresorufin. This indicates no functional differences between the CYPIAI forms and support the data by us and other investigators, that subjects carrying this allele do not have an increased risk for lung cancer.