Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity.

Ketoconazole (KC), an antifungal agent, rarely causes severe liver injury when orally administered. It has been reported that KC is mainly hydrolyzed to N-deacetyl ketoconazole (DAK), followed by the N-hydroxylation of DAK by flavin-containing monooxygenase (FMO). Although the metabolism of KC has been considered to be associated with hepatotoxicity, the responsible enzyme(s) remain unknown.

Pathogenetic analyses of carbamazepine-induced liver injury in F344 rats focused on immune- and inflammation-related factors.

Drug-induced liver injury is one of the major reasons for a drug to be withdrawn postmarketing. Carbamazepine (CBZ), an anticonvulsant agent, has been reported rarely to cause liver failure in humans. We recently generated a rat model of CBZ-induced liver injury using F344 rats for five consecutive days of CBZ administration combined with a glutathione (GSH) depletor, L-buthionine S,R-sulfoximine, treatment.

Comparison of substrate specificity among human arylacetamide deacetylase and carboxylesterases.

Human arylacetamide deacetylase (AADAC) is an esterase responsible for the hydrolysis of some drugs, including flutamide, indiplon, phenacetin, and rifamycins. AADAC is highly expressed in the human liver, where carboxylesterase (CES) enzymes, namely, CES1 and CES2, are also expressed. It is generally recognized that CES1 prefers compounds with a large acyl moiety and a small alcohol or amine moiety as substrates, whereas CES2 prefers compounds with a small acyl moiety and a large alcohol or amine moiety.

Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats.

Carbamazepine (CBZ) is widely used as an antiepileptic agent and causes rare but severe liver injury in humans. It has been generally recognized that reactive metabolites formed via the metabolic activation reaction contribute to the onset of liver injuries by several drugs. However, the role of CBZ metabolism in the development of liver injury is not fully understood.

A novel mouse model for phenytoin-induced liver injury: involvement of immune-related factors and P450-mediated metabolism.

Drug-induced liver injury is an important issue for drug development and clinical drug therapy; however, in most cases, it is difficult to predict or prevent these reactions due to a lack of suitable animal models and the unknown mechanisms of action. Phenytoin (DPH) is an anticonvulsant drug that is widely used for the treatment of epilepsy. Some patients who are administered DPH will suffer symptoms of drug-induced liver injury characterized by hepatic necrosis.