Toxicokinetics and toxicity of thioacetamide sulfoxide: a metabolite of thioacetamide.
Thioacetamide (TA) is bioactivated by CYP2E1 to TA sulfoxide (TASO), and to the highly reactive sulfdioxide (TASO(2)), which initiates hepatic necrosis by covalent binding. Previously, we have established that TA exhibits saturation toxicokinetics over a 12-fold dose range, which explains the lack of dose-response for bioactivation-based liver injury. In vivo and in vitro studies indicated that the second step (TASO-->TASO(2)) of TA bioactivation is less efficient than the first one (TA-->TASO). The objective of the present study was to specifically test the saturation of the second step of TA bioactivation by directly administering TASO, which obviates the contribution from first step, i.e. TA-->TASO. Male SD rats were injected with low (50mg/kg, ip), medium (100mg/kg) and high (LD(70), 200mg/kg) doses of TASO. Bioactivation-mediated liver injury that occurs in the initial time points (6 and 12h), estimated by plasma ALT, AST and liver histopathology over a time course, was not dose-proportional. Escalation of liver injury thereafter was dose dependent: low dose injury subsided; medium dose injury escalated upto 36h before declining; high dose injury escalated from 24h leading to 70% mortality. TASO was quantified in plasma by HPLC at various time points after administration of the three doses. With increasing dose (i.e., from 50 to 200mg/kg), area under the curve (AUC) and C(max) increased more than dose proportionately, indicating that TASO bioactivation exhibits saturable kinetics. Toxicokinetics and initiation of liver injury of TASO are similar to that of TA, although TASO-initiated injury occurs at lower doses. These findings indicate that bioactivation of TASO to its reactive metabolite is saturable in the rat as suggested by previous studies with TA.