Pharmacogenetic analysis in sickness and in health - for better or for worse

Abstract: An individual's pharmacogenetic constitution may predict response to drugs, hormones and toxins, and might be a susceptibility factor for disease. Pharmacogenetic diversity is especially pronounced for drug metabolising enzymes. In these studies the following five enzymes have been genotyped: N-acetyltransferase 2 (NAT2), sparteine/debrisoquine hydroxylase (CYP2D6), mephenytoin hydroxylase (CYP2C19), steroid 17α-hydroxylase (CYP17), and glutathione S-transferase P1 (GSTP1).A simplified method for genotyping NAT2 was verified by phenotyping with isoniazid. All phenotypes: slow, intermediate and fast acetylators were correctly identified by genotyping. This method was used to genotype control subjects and patients who reacted to sulphasalazine with agranulocytosis. The incidence of slow acetylation was equal in agranulocytosis patients and population-based controls. However, the incidence of slowacetylation was significantly reduced in patients who tolerated sulphasalazine compared with both agranulocytosis patients and population-based controls.Different genotypes of the enzymes NAT2, CYP2D6, CYP2C19, GSTP1 and CYP17 were studied as possible susceptibility factors for prostate cancer in a case-control study. No association was found between prostate cancer and NAT2, CYP2D6, CYP2C19 orGSTP1 genotypes. A certain genotype of CYP17, encoding a key enzyme in testosterone synthesis, was associated with prostate cancer, a finding that warrants further studies. CYP2D6 is not considered to be an inducible enzyme, but phenotyping of pregnant women showed that CYP2D6 activity is increased during pregnancy. This may be caused by enzyme induction, suggesting possible impact on drug treatment during pregnancy. In the future, as more pharmacogenetic information becomes available, predicting individual drug responses will become an essential part of therapy.