Deficiency in cytosolic malic enzyme does not increase acetaminophen-induced hepato-toxicity.
Cytosolic malic enzyme (ME-1) is a nicotinamide adenine dinucleotide phosphate (NADP)-dependent enzyme that generates NADPH. The activity of this enzyme, the reversible oxidative decarboxylation of malate to yield pyruvate, links glycolytic pathway to citric acid cycle. The high level of ME-1 expression in liver, and its involvement in NADPH production, suggests reduced ME-1 activity might compromise hepatic production of reduced glutathione (GSH) by the NADPH-dependent enzyme glutathione reductase, and hence affect xenobiotic detoxification. The role of ME-1 in liver detoxification was evaluated in Mod1 deficient mice (mod1(-/-)) by evaluating their sensitivity to acetaminophen-induced liver injury. The results show that mod1(-/-) mice are not more sensitive to acetaminophen hepato-toxicity. Although GSH levels were initially depleted more in the mod1(-/-) liver than in wild-type controls, the GSH levels recovered quickly. In conclusion, our data indicate that ME-1 deficiency does not adversely affect GSH-dependent detoxification.
Qian
Su
S
Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ, USA. su_qian@merck.com
Mumick
Sheena
S
Nizner
Peter
P
Tota
Michael R
MR
Menetski
Joseph
J
Reitman
Marc L
ML
Macneil
Douglas J
DJ
D000082:Acetaminophen / Q000633:toxicity*; D000700:Analgesics / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000473:pathology; D003600:Cytosol / Q000201:enzymology; D005838:Genotype; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009249:NADP / Q000378:metabolism
D000700:Analgesics; D000082:Acetaminophen; D009249:NADP; D008291:Malate Dehydrogenase; D005978:Glutathione