Hepatobiliary transport and metabolism of the methylmercury-glutathione complex

Thesis/Dissertation · Sat Dec 31 04:00:00 EST 1994

OSTI ID:68640

Dutczak, W J

Biliary excretion, followed by fecal elimination, is a major route for the elimination of metals, including methylmercury; however, the mechanisms for the hepatobiliary transport and metabolism of these compounds have not been identified. The goal of this research was to characterize the mechanism by which methylmercury, a highly neurotoxic environmental contaminant, is transported across the canalicular membrane into bile and to investigate the fate of this metal within the biliary tree. Methylmercury is eliminated predominately through biliary excretion and undergoes extensive enterohepatic cycling. Because methylmercury is believed to be transported across the canalicular membrane into bile as a glutathione complex (CH{sub 3}Hg-SG), its fate may be similar to that of glutathione (GSH). GSH is transported into bile by an electrogenic, carrier mediated transport system, where it is catabolized by the luminal enzymes {gamma}-glutamyltransferase ({gamma}-GT) and dipeptidases yielding glutamate, cysteine, and glycine, and these products are then partially reabsorbed from the biliary tree. To investigate the mechanism by which CH{sub 3}Hg-SG is transported into bile, CH{sub 3}{sup 203}Hg-SG transport was characterized using liver plasma membrane vesicles derived from the canalicular domain of rat hepatocytes. CH{sub 3}Hg-SG uptake was independent of either ATP or a Na{sup +} gradient; however, uptake was stimulated by an induced electrical potential. CH{sub 3}Hg-SG transport was saturable with both high (K{sub m} = 11.9 {+-} 1.6 {mu}M) and low (K{sub m} = 1.47 {+-} 0.22 mM) affinity components. Uptake of this complex was inhibited by GSH and various GSH conjugates but not by GSSG, bile acids, amino acids, or p-glycoprotein substrates. Furthermore, GSH competitively inhibited and trans-stimulated CH{sub 3}Hg-SG uptake.

• Research Organization: Rochester Univ., NY (United States)
• OSTI ID: 68640
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
56 BIOLOGY AND MEDICINE
APPLIED STUDIES
BILIARY TRACT
BIOLOGICAL HALF-LIFE
BIOLOGICAL PATHWAYS
DYNAMIC FUNCTION STUDIES
EXCRETION
GLUTATHIONE CONJUGATES
LIVER
METABOLIC ACTIVATION
METABOLISM
METHYLMERCURY
TOXICITY