ANTIMITOTIC INTERVENTION WITH COLCHICINE ALTERS THE OUTCOME OF O-DCB-INDUCED HEPATOTOXICITY IN FISCHER-344 RATS

Although, hepatotoxic injury of 1,2-dichlorobenzene (o-DCB) is greater in Fischer 344 (F344) as compared to Sprague-Dawley (S-D) rats, this interstrain difference does not transcend into any difference in letha l effects of o-DCB. Interstrain difference in compensatory tissue repa ir has been suggested as the underlying mechanism for the lack of stra in differences in lethality (S.G. Kulkarni, H. Duong, R. Gomila, and H .M. Mehendale, Strain differences in tissue repair response to 1,2-dic hlorobenzene. Archives of Toxicology 1996; 70: 714-723). If higher tis sue repair in F344 rats compensates for more severe liver injury, then antimitotic intervention after infliction of o-DCB-induced liver inju ry should lead to lethality in F344 rats. Colchicine (CLC, 1 mg/kg) fu nctions as an effective antimitotic agent and does not cause any side effects apart from suppressing cellular proliferation. Two groups of m ale F344 rats (160-190 g) received a single dose of 0.6 ml o-DCB/kg: 3 0 h later one group of rats received CLC (1 mg/kg; i.p.) and the other received distilled water (1 ml/kg; i.p.). Liver injury was assessed b y measuring plasma ALT and SDH activity, liver histopathology, and liv er regeneration was estimated by [H-3]thymidine incorporation into hep atonuclear DNA and proliferating cell nuclear antigen (PCNA) assay in both groups. Similar liver injury was noted in both the o-DCB + vehicl e and o-DCB + CLC treated F344 rats at 36 h indicating that CLC does n ot interfere with the uptake, bioactivation and causation of injury by o-DCB. S-phase synthesis which occurred at 36 h in the o-DCB + vehicl e group was blocked in the o-DCB + CLC group. CLC administration 6 h p rior to S-phase stimulation selectively abolished S-phase stimulation at 36 h, and led to 50% lethality. Since the effect of CLC antimitosis was transient, S-phase synthesis occurring at 48 h was not blocked an d was sustained up to 72 h thereby allowing the other 50% of rats to o vercome liver injury induced by o-DCB and survive the lethal outcome. These findings suggest that a significantly higher rate of compensator y tissue repair in F344 rats enables them to overcome more severe live r injury inflicted by o-DCB. (C) 1997 Elsevier Science Ireland Ltd.