Bilirubin animal models

The widespread use of isoniazid prophylaxis for tuberculosis has focused attention on the liver injury caused by this drug. About 20% of patients treated with isoniazid will show elevated blood concentrations of liver enzymes and bilirubin that subside as treatment is continued (25). However/ clinical hepatitis develops in some patientS/ and these reactions can prove fatal. Current understanding of the mechanism of isoniazid-induced hepatotoxicity is based on the metabolic pathways shown in Figure 16.6 (26/ 27). It has been demonstrated in an animal model that hepatotoxicity is correlated with plasma concentrations of hydrazine but not of acetylhydrazine or isoniazid (28)/ and that pretreatment with an amidase inhibitor can prevent toxicity (27). However/ it is postulated that hydrazine is further metabolized to a chemically reactive he pa to toxin by the cytochrome P450 system/ and in vitro studies with hepatocytes have implicated CYP2E1 as the cytochrome P450 isoform responsible for cytotoxic metabolite formation (29). 

Several different animal models have been utilized to examine the effects of hyperbilirubinemia in vivo. The primary focus was to elevate bilirubin levels to the point of kemicterus, then examine changes in cerebral metabolism. 

The fact that jaundice was noticeably absent in adolescents treated in a prophylactic manner with isoniazid, despite the occurrence of abnormal SGPT values, prompted Cohen and McNamara to investigate the effects of isoniazid on bilirubin metabolism (3 ) using rats as an experimental model. They found that hepatic bilirubin glucuronyl-transferase activity was enhanced in the animals receiving the drug. Such enhanced activity could account for the absence of hyperbilirubinaemia in subjects with biochemical evidence of hepatic dysfunction whilst receiving isoniazid. 

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