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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004400-03
Application #
3252549
Study Section
Toxicology Study Section (TOX)
Project Start
1987-08-01
Project End
1992-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
School of Medicine & Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Hinchman, C A; Truong, A T; Ballatori, N (1993) Hepatic uptake of intact glutathione S-conjugate, inhibition by organic anions, and sinusoidal catabolism. Am J Physiol 265:G547-54
Ballatori, N; Truong, A T (1992) Glutathione as a primary osmotic driving force in hepatic bile formation. Am J Physiol 263:G617-24
Ballatori, N; Boyer, J L (1992) Taurine transport in skate hepatocytes. II. Volume activation, energy, and sulfhydryl dependence. Am J Physiol 262:G451-60
Kerper, L E; Ballatori, N; Clarkson, T W (1992) Methylmercury transport across the blood-brain barrier by an amino acid carrier. Am J Physiol 262:R761-5
Dutczak, W J; Ballatori, N (1992) gamma-Glutamyltransferase-dependent biliary-hepatic recycling of methyl mercury in the guinea pig. J Pharmacol Exp Ther 262:619-23
Simmons, T W; Anders, M W; Ballatori, N (1992) L-cysteine and S-(1,2-dichlorovinyl)-L-cysteine transport in rat liver canalicular membrane vesicles: potential reabsorption mechanisms for biliary metabolites of glutathione and its S-conjugates. J Pharmacol Exp Ther 262:1182-8
Ballatori, N (1991) Mechanisms of metal transport across liver cell plasma membranes. Drug Metab Rev 23:83-132
Dutczak, W J; Clarkson, T W; Ballatori, N (1991) Biliary-hepatic recycling of a xenobiotic: gallbladder absorption of methyl mercury. Am J Physiol 260:G873-80
Hinchman, C A; Matsumoto, H; Simmons, T W et al. (1991) Intrahepatic conversion of a glutathione conjugate to its mercapturic acid. Metabolism of 1-chloro-2,4-dinitrobenzene in isolated perfused rat and guinea pig livers. J Biol Chem 266:22179-85
Ballatori, N; Truong, A T (1990) Cholestasis, altered junctional permeability, and inverse changes in sinusoidal and biliary glutathione release by vasopressin and epinephrine. Mol Pharmacol 38:64-71

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