Transferase Variants One of the most extensively studied phase II polymorphisms is the PM trait for thiopurine S-methyltransferase (TPMT). TPMT bioinactivates the antileukemic drug 6-mercaptopurine. Further, 6-mercaptopurine is itself an active metabolite of the immunosuppressive azathioprine. Homozygotes for alleles encoding the inactive TPMT (1 in 300 individuals) predictably exhibit severe and potentially fatal pancytopenia on standard doses of azathioprine or 6-mercaptopurine. On the other hand, homozygotes for fully functional alleles may display less antiinflammatory or antileukemic effect with the drugs. N-acetylation is catalyzed by hepatic N-acetyl transferase (NAT), which represents the activity of two genes, NAT-1 and NAT-2. Both enzymes. | Chapter 005. Principles of Clinical Pharmacology Part 9 Transferase Variants One of the most extensively studied phase II polymorphisms is the PM trait for thiopurine S-methyltransferase TPMT . TPMT bioinactivates the antileukemic drug 6-mercaptopurine. Further 6-mercaptopurine is itself an active metabolite of the immunosuppressive azathioprine. Homozygotes for alleles encoding the inactive TPMT 1 in 300 individuals predictably exhibit severe and potentially fatal pancytopenia on standard doses of azathioprine or 6-mercaptopurine. On the other hand homozygotes for fully functional alleles may display less antiinflammatory or antileukemic effect with the drugs. N-acetylation is catalyzed by hepatic A-acetyl transferase NAT which represents the activity of two genes NAT-1 and NAT-2. Both enzymes transfer an acetyl group from acetyl coenzyme A to the drug NAT-1 activity is generally constant while polymorphisms in NAT-2 result in individual differences in the rate at which drugs are acetylated and thus define rapid acetylators and slow acetylators. Slow acetylators make up 50 of European- and African-derived populations but are less common among Asians. Slow acetylators have an increased incidence of the drug-induced lupus syndrome during procainamide and hydralazine therapy and of hepatitis with isoniazid. Induction of CYPs . by rifampin also increases the risk of isoniazid-related hepatitis likely reflecting generation of reactive metabolites of acetylhydrazine itself an isoniazid metabolite. Individuals homozygous for a common promoter polymorphism that reduces transcription of uridine diphosphate glucuronosyltransferase UGT1AT have benign hyperbilirubinemia Gilbert s syndrome Chap. 297 . This variant has also been associated with diarrhea and increased bone marrow depression with the antineoplastic prodrug irinotecan whose active metabolite is normally detoxified by this UGT1A1-mediated glucuronidation. Variability in the Molecular Targets with Which Drugs .
