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 depletion of ATP in metabolically compromised cells causes a decreased synthesis of the co-substrates, adenosine 3'-phosphate 5'-phosphosulfate (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 cyanide m-chlorophenylhydrazone, and 2,4-dinitrophenol. Hepatic ATP levels 30 min after administration of the inhibitors 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 min after administration of the inhibitors. Thus, it does not appear possible to deplete hepatic ATP in vivo by means of mitochondrial inhibitors to the extent necessary to affect basal levels of UDP-glucuronic acid, PAPS, and glutathione. PAPS levels increased after administration of 2,4-dinitrophenol. This was shown to be a property shared with phenolic inhibitors of phenol sulfotransferase.