Читать книгу Transporters and Drug-Metabolizing Enzymes in Drug Toxicity - Albert P. Li - Страница 42

NAT2 is expressed predominantly in the liver. More than 100 NAT2 alleles are being cataloged by the Arylamine N‐acetyltransferase Gene Nomenclature Committee. Pharmacogenetic studies of NAT2 largely have focused on the anti‐tuberculosis drug isoniazid. NAT2 is critical to the clearance of isoniazid and its metabolites, including acetylhydrazine and hydrazine, which have been associated with hepatotoxicity [102, 103]. Patients carrying NAT2 variants with decreased enzymatic function (slow acetylator) have been reported to have higher isoniazid exposure and increased risk of DILI during anti‐tuberculosis treatment [52, 104, 105]. This suggests that genotype‐based dosing for isoniazid might be of clinical relevance. In addition to the NAT2 pathway, an alternative pathway comprised of CYP2E1 and GST plays a role in the clearance of isoniazid. CYP2E1 polymorphisms also have a suggested association with isoniazid hepatotoxicity [51, 106], however, with inconsistent evidence [104, 107]. The pharmacogenetic association remains uncertain.