Physiological and Biochemical Metabolic Study Related to DBCP-induced Hepatic Necrosis in Rats

Abstract

The physiological and biochemical metabolic fate of 1, 2-dibromo-3-chloropropane (DBCP) was studied in relation to the mammalian toxicity of the chemical. On oral administration of 14C-DBCP to male rats at 20 to 400mg/kg which was the lethal dose causing death in 24hr with a severe necrotic lesion in the liver and kidney (inner cortex), the 14C at all dose levels maldistributed in these target organs (and the target organ site). Radioactive material covalently bound to proteins was the predominant radioactive component in these target organs and dose-dependently increased with a concomitant severe depression of hepatic glutathione (GSH). Formation of 14C-urea which implies a de novo synthesis of 14C-labeled proteins and nucleic acids via the C1-pool was not detected. Alkylating potential of DBCP was evidenced by in vitro binding experiments in which 14C-incorporation into the liver-9, 000g supernatant and microsomal (ms) proteins required an oxidative metabolic transformation of DBCP by ms-cyt P450 enzyme system, but this was not dependent on the protein synthesis. Low molecular-weight SH compounds such as GSH prevented the alkylation of the macromolecules; however, no prooxidant action indicating involvement of a DBCP-free radical was detected. A low concentration of 1, 1, 1-trichloro-propane-2, 3-oxide, an inhibitor of ms-epoxide hydrase, stimulated the alkylation of the macromolecules. Thus, DBCP was concluded to be oxidatively converted into a reactive epoxide (s) and covalently bound with the nucleophilic sites of the cellular macromolecules in vitro and in vivo. Investigations on the toxicological and metabolic alterations after pretreatment (ip) of rats with phenobarbital, SKF-525A, and GSH demonstrated that the severity of the necrotic lesion in the centrilobular hepatocytes induced by 400mg/kg of DBCP was closely dependent on the alkylation of the hepatic macromolecules.