Acetylonium ion acetyl radical ketene Toxic

Figure 4 Metabolism of isoniazid.

produces hydrazine that could cause liver injury (115). Metabolism of isoniazid through this minor pathway is increased 10-fold in slow acetylators, especially when given with rifampicin (116).

Two human NAT functional genes (NAT1 and NAT2) and one pseudogene (NATP) have been cloned (117). NAT2 is polymorphic in humans and has a 10-times lower Km for aromatic amines than that of NAT1. The presence of any two of the several variant alleles of the NAT2 gene leads to the slow acetylator phenotype, whereas fast acetylators have one or more wild-type NAT2*4 alleles (117). Acetylation activity in vitro is progressively reduced in association with the NAT2*4 > NAT2*7 > NAT2*6 > NAT2*5 alleles (118). In a recent study involving 224 patients who received antituberculosis therapy, patients possessing the NAT2 genotypes associated with slow acetylation were four times more likely to develop isoniazid-induced hepatotoxicity (105). In addition, the hepatic injury in slow acetylators was more severe than that seen in rapid acetylators. Patients with the NAT2*6/6 and NAT2*6/7 genotypes had a significantly higher risk than those with other genotypes.

Indinavir-induced hyperbilirubinemia. Indinavir is a viral protease inhibitor used in the treatment of HIV infection. Indinavir therapy is associated with unconjugated hyperbilirubinemia in 6% to 25% of the subjects (119,120). This could lead to unnecessary investigations and inappropriate withdrawal of the medication. Although indinavir is predominantly metabolized by the CYP450 enzyme system, the drug is also a substrate for UGT (121). Indinavir competitively inhibits conjugation of bilirubin by UGT1A1 in rat hepatoma cell culture (122). In experiments with Gunn rats, a strain deficient in hepatic bilirubin-conjugating activity caused by a mutation in the UGT1A1 gene, administration of indinavir results in a greater elevation of serum bilirubin in heterozygous ( j/+) animals than in wild-type controls (+ /+) (122). Consistent with this, an increase in serum bilirubin following indinavir therapy has been found to be more pronounced in patients with one or more variant UGT1A1 alleles (122). Therefore, hyperbilirubinemia secondary indinavir is likely to be most pronounced in individuals with reduced hepatic UGT activity, such as those with Gilbert's syndrome.

Immunologic Idiosyncrasy. The second group of genetic factors influencing susceptibility to immune-mediated hepatic drug reactions are those involved in immune regulation. Genetic polymorphisms in the major histocompatibility complex (MHC) are the most obvious example. The presence or absence of a given human leukocyte antigen (HLA) molecule may determine the efficient presentation of an alkylated immunogenic peptide. Associations have been reported between HLA A11 and hepatotoxicity due to halothane, tricyclic antidepressants and diclofenac; HLA DR6 and liver injury secondary to chlorpromazine and nitrofurantoin, and HLA B8; and clometacine-induced hepatitis (123). However, patients with liver injury due to a heterogeneous group of drugs were included in this study, and, hence, the association of the genotype with the liver injury should be considered to be preliminary and requires replication.

Co-amoxiclav-induced jaundice. Co-amoxiclav is a commonly used antibiotic, that causes cholestatic jaundice. The frequency of this ADR is about one case per 5000-80,000 prescriptions, and the risk increases with advancing age (124-126). Clavulanic acid rather than amoxicillin has been considered to be responsible for immu-noallergic hepatitis. Two case-control studies involving Caucasians have demonstrated that co-amoxiclav-induced jaundice is strongly associated with the HLA DRB1 *1501-DRB5*0101-DQB1*0602 haplotype (126,127). Subjects carrying the extended haplotype had a ninefold higher risk of cholestasis (126). These findings suggest that HLA class II molecules are important in presenting the drug-metabolite to the T-cell receptor of CD4+ helper T-cells with the subsequent stimulation of B-cells and cytotoxic T-cells and development of the immune reaction.

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The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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