DBCP の毒性に関する代謝的研究

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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 ^<14>C-DBCP to male rats at 20 to 400mg/kg which was the lethal dose causing death in 24 hr with a severe necrotic lesion in the liver and kidney (inner cortex), the ^<14>C 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 ^<14>C-urea which implies a de novo synthesis of ^<14>C-labeled proteins and nucleic acids via the C_1-pool was not detected. Alkylating potential of DBCP was evidenced by in vitro binding experiments in which ^<14>C-incorporation into the liver 9, 000g supernatant and microsomal (ms) proteins required an oxidative metabolic transformation of DBCP by ms-cyt P_<450> 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.
日本農薬学会の論文
1981-08-20

DBCP の毒性に関する代謝的研究

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