In vivo and in vitro 1-methylxanthine metabolism in the rat. Evidence that the dehydrogenase form of xanthine oxidase predominates in intact perfused liver.
Concentrations of 1-, 3-, and 7-methylxanthine and their uric acid metabolites were measured in plasma and brain affusate 20 min after ip injection of the monomethylxanthines into rats. 3-Methylxanthine was not metabolized to 3-methyluric acid. Similar concentrations of 7-methylxanthine and 7-methyluric acid were detected in both plasma and brain affusate. The oxidation of 1-methylxanthine to 1-methyluric acid occurred so rapidly that the parent compound could not be detected in plasma, and only low concentrations could be detected in brain. Similar patterns in rates of metabolism (1-methyl- greater than 7-methyl- much greater than 3-methylxanthine) were observed in both intact animals and perfused rat liver. The metabolism of 1-methylxanthine to 1-methyluric acid in perfused livers could be explained on the basis of the dehydrogenase form of xanthine oxidase. This conclusion is supported by the observations that the stoichiometry between oxygen utilization and methylurate formation was not consistent with catalysis by the oxidase form of the enzyme and that NADH formed from the metabolism of ethanol strongly inhibited 1-methylxanthine oxidation. In perfused liver, anaerobic conditions decreased rates of 1-methylxanthine metabolism by only 24%. These data demonstrate the presence of oxidizing substrates other than oxygen and NAD+ which are capable of maintaining xanthine oxidase activity during hypoxia. Moreover, rates of 1-methylxanthine metabolism during anoxia could be restored to normal, aerobic values by the infusion of pyruvate, which increased hepatic levels of NAD+. These data demonstrate that changes in the hepatic oxidation-reduction state may dramatically affect rates of xanthine oxidase-dependent metabolism in intact cells.
D000818:Animals; D002110:Caffeine / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D007658:Ketone Oxidoreductases / Q000032:analysis*; D008099:Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D014527:Uric Acid / Q000031:analogs & derivatives / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000032:analysis*; D014969:Xanthine Oxidase / Q000032:analysis*; D014970:Xanthines / Q000378:metabolism*
D014970:Xanthines; D014527:Uric Acid; C008514:methylxanthine; C030530:1-methyluric acid; D002110:Caffeine; D000431:Ethanol; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D007658:Ketone Oxidoreductases