COLCHICINE ANTIMITOSIS ABOLISHES RESILIENCY OF POSTNATALLY DEVELOPINGRATS TO CHLORDECONE-AMPLIFIED CARBON-TETRACHLORIDE HEPATOTOXICITY ANDLETHALITY

We have previously reported that rats are resilient to the hepatotoxic and lethal combination of chlordecone (CD) and carbon tetrachloride ( CCl4) during early postnatal development. The overall findings pointed to stimulated cell division and tissue repair mechanisms as the under lying cause of resistance. The objective of the current study was to i nvestigate if the antimitotic effect of colchicine (CLC) abolishes thi s resiliency to CD + CCl4 by inhibiting ongoing and stimulated cell di vision. We used 45-day-old rats in this study because this age group e xhibited partial sensitivity to CD + CCl4 in our previous studies. Mal e Sprague-Dawley rats were treated with a single low intraperitoneal d ose of CCl4 (100 mu l/kg) or corn oil after exposure to either 10 ppm CD in the diet or a normal diet (ND) for 15 days. CLC (1 mg/kg) was ad ministered 6 or 30 hr after CCl4 to ND or CD rats, respectively. Admin istration of CLC resulted in increased CCl4-induced mortality from 25% to 85% in rats pretreated with CD, in contrast to 100% survival in ND rats. Liver injury was assessed by plasma alanine transaminase (ALT) and sorbitol dehydrogenase (SDH) elevations as well as by histopatholo gy. Hepatocellular regeneration was assessed by H-3-thymidine (H-3-T) incorporation into hepatonuclear DNA and proliferating cell nuclear an tigen (PCNA) studies during 0-96 hr after CCl4. Administration of CLC to ND + CCl4 rats resulted in a slight delay in cell division and tiss ue repair, as indicated by H-3-T incorporation and PCNA, thereby leadi ng to prolonged liver injury as revealed by elevations in plasma ALT, SDH, and histopathological lesions. In contrast, CLC administration to CD + CCl4-treated rats further delayed and diminished cell division b y 80%, which led co unrestrained progression of CCl4-induced liver inj ury, resulting in 85% mortality. These findings underscore the importa nce of ongoing and toxicant-stimulated cell division and tissue repair mechanisms in hepatotoxicity, and the need for the inclusion of age f actors in risk assessment of exposure to environmental and other chemi cals.