Halomethane-chlordecone (CD) interactive hepatotoxicity--current concepts on the mechanism.
Why is a low dose of toxic chemical nontoxic? What makes a larger dose of the same chemical toxic? Extensive work done to understand the mechanism of halomethane hepatotoxicity and its potentiation by chlorinated insecticide, chlordecone has resulted in the understanding of these basic tenets of toxicology. Studies suggest that ordinarily a small dose of halomethane causes limited liver injury which is accompanied by stimulated tissue repair enabling complete recovery from injury before manifestation. A large dose of halomethane becomes toxic due to suppressed tissue repair, which permits injury to progress in an unchecked fashion. Exposure to very low levels of chlordecone results in highly exaggerated toxicity of ordinarily nontoxic doses of halomethane because of suppressed hepatocellular regeneration and restoration, permitting the progression of liver injury ultimately resulting in liver failure and animal mortality. This concept is further supported by the observation that, while exposure to even high levels of phenobarbital and subsequent low nontoxic doses of halomethane results in greater level of initial liver injury, tissue repair is not completely suppressed; it is slightly postponed by 24 hr, but then much higher rate of tissue repair ensures and consequently enables the animals to completely recover from liver injury and survive. Thus, whether initiation of tissue repair processes occurs or not is the critical determinant in the ultimate manifestation of hepatotoxicity and its end result of either animal death or recovery and survival. Currently understood 'Mechanisms of toxicity' adequately explain only how toxic injury begins. These mechanisms do not permit us to predict the ultimate outcome of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Rao
S B
SB
Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe 71209-0470.
Mehendale
H M
HM
D000818:Animals; D007631:Chlordecone / Q000633:toxicity*; D004347:Drug Interactions; D004357:Drug Synergism; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008115:Liver Regeneration; D008697:Methane / Q000031:analogs & derivatives* / Q000633:toxicity*; D013045:Species Specificity
D006846:Hydrocarbons, Halogenated; D008697:Methane; D007631:Chlordecone