THE EFFECT OF INHIBITORS OF MITOCHONDRIAL ENERGY PRODUCTION ON HEPATIC GLUTATHIONE, UDP-GLUCURONIC ACID, AND ADENOSINE 3’-PHOSPHATE-5’- PHOSPHOSULFATE CONCENTRATIONS

The hepatic conjugation of xenobiotics with sulfate, glucuronic acid, and glutathione is decreased In vitro by compounds that impair cellular energy production. The proposed mechanism is that deple-don of ATP in metabolically compromised cells causes a decreased synthesis of the co-substrates, adenosine 3’-phosphate 5’-phospho-sulfate (PAPS), UDP-glucuronic acid, and glutathione. This proposal was examined In vivo by quantitating hepatic adenine nucleotides and co-substrates in rats treated with the following inhibitors of mitochondrial ATP production: rotenone, antimycin A, carbonyl cya-nide m-chlorophenylhydrazone, and 2,4-dinitrophenol. Hepatic ATP levels 30 mm after administration of the inhibftors were about 30% of control. Hepatic energy charge (ATP + 0.5 x ADP)/(ATP + ADP + AMP) was significantly reduced by each inhibitor. Unexpectedly, UDP-glucuronic acid, PAPS, and glutathione concentrations were not reduced at 30 or 60 mm after administration of the inhibitors. Thus