Glutathione depletion kinetics with acetaminophen. A simulation study.
A tubular-flow model with known published parameters on glutathione (GSH) synthesis, degradation, and transport was developed to examine the distributed-in-space bimolecular reaction of GSH conjugation with acceptor substrates. Simulations were performed to obtain the vascular and intracellular GSH concentrations in the absence and presence of acetaminophen. Zonal localization of GSH was found to be effectively modified upon varying the activities for GSH synthesis and degradation along the sinusoidal flow path. A periportal (zone 1) GSH distribution resulted when GSH synthetic activity was distributed anterior to the degradation activity (models A and D); a perivenous (zone 3) GSH enrichment existed when these activities were reversed (model B), whereas when the synthetic and degradation activities for GSH were homogeneously distributed (model C), GSH concentration was unchanged in all zones. Although the zonation of GSH was model-dependent (models A-D ), only minor differences were found to exist for the length-averaged tissue GSH concentration (5.8-6 mumol/g liver) and the outflow of the liver (approximately 15 microM). With acetaminophen, a substrate known to deplete GSH via its reactive intermediate, N-acetyl-p-quinoneimine (NAPQI), acinar GSH patterns were not greatly perturbed at concentrations < 1 mM. At 10 mM acetaminophen, however, differential patterns of GSH zonal depletion were observed among models, although there was virtually no difference in the length-averaged intracellular GSH concentration (3 mumol/g liver) nor in the formation of the acetaminophen GSH adduct, with the latter being rate-limited by the bioactivation of acetaminophen to NAPQI.(ABSTRACT TRUNCATED AT 250 WORDS)
Chiba
M
M
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Pang
K S
KS
D000082:Acetaminophen / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism / Q000493:pharmacokinetics; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D007097:Imines / Q000378:metabolism / Q000493:pharmacokinetics; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism; D008432:Mathematical Computing; D008954:Models, Biological; D010477:Perfusion; D051381:Rats
D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione