Despite our improved understanding of the potential health hazards of methylmercury (MeHg) exposure, this metal continues to be a toxin of widespread environmental concern. Studies conducted over the past two decades have convincingly demonstrated that the only way to prevent or ameliorate toxicity, once MeHg has been ingested, is to accelerate its removal from the body. The principal pathway for eliminating MeHg is the gastrointestinal tract: fecal excretion accounts for approximately 90% of the total excretion in humans or animals exposed to methylmercury, and therefore effectively determines the biological half-time. Gastrointestinal excretion is in turn determined primarily by biliary secretion. The proposed studies are designed to elucidate the processes invovled in the transport of MeHg compounds into bile. Although the present studies will deal exclusively with MeHg, it is anticipated that the basic mechanisms that underly the metabolism and transport of MeHg may be applicable to other metals with similar physiochemical properties. The hepatobiliary transport of MeHg is considered to consist of at least four separate processes: a) hepatic uptake, b) intracellular translocation and metabolism, c) transport into bile, and d) postsecretory modifications within the biliary tree and in the gallbladder. The specific objectives of the proposed studies are to characterize these processes at the cellular and subcellular level. Priority will be given to those processes most amendble to experimental manipulation: 1) Fate of MeHg within the biliary tree: Is MeHg reabsorbed such that an intrahepatic cycle exists? 2) role of the gallbladder: To what extent is biliary MeHg transported on the same membrane carrier(s) as glutathione (GSH) and its conjugates? 4) Transport from plasma into the liver cell: Is MeHg transported by specific carriers for endogenous substrates such as albumin or amino acids, or GSH? 5) Intracellular transport: Is it necessary to postulate a specific step or process other than diffusion, e.g. transport by ligandin? The experimental methods to be used to address these questions are a) in vivo studies using retrograde intrabiliary infusion in rats and rabbits, b) rat liver canalicular and basolateral plasma membrane vesicles, and c) the isolated perfused rat liver preparation.
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