Coordinate modulation of murine hepatic xanthine oxidase activity and the cytochrome P-450 system by interferons.
The role of xanthine oxidase (XO) in the interferon (IFN)-dependent modulation of the hepatic cytochrome P-450 system was assessed in SENCAR mice. Intraperitoneal administration of 10(4)-10(5) units of IFN-gamma resulted in dose-dependent increases in hepatic XO activities. XO activity was significantly elevated within 12 h of IFN-gamma treatment, and reached a maximum between 24-48 h, and returned to basal levels within 72-96 h. Although the kinetics of increase and decline of XO activity correlated with the loss and subsequent recovery of hepatic P-450 levels, there was no quantitative correlation between hepatic XO activity and P-450 content. Comparable results were obtained in mice pretreated with the P-450 inducer Aroclor 1254 3 days prior to IFN-gamma administration. The increases in XO activity following IFN-gamma treatment were the consequence of increases in xanthine dehydrogenase (XD), and the conversion of XD to XO. The ad libitum administration of allopurinol to IFN-gamma-treated mice reduced XO specific activity to approximately 4% of the basal activity of control mice, but did not prevent reductions in cytochrome P-450 levels or the activities of two P-450 dependent monooxygenases. Collectively, these data suggest that the reductions in the hepatic P-450 system noted after IFN administration are not a consequence of elevated XO activities.
University of Texas System Cancer Center, Science Park-Research Division, Smithville 78957.
J J
JJ
Reiners
A R
AR
Cantu
T A
TA
Rupp
D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007372:Interferons / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D051379:Mice; D014968:Xanthine Dehydrogenase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism*
D001140:Aroclors; D020111:Chlorodiphenyl (54% Chlorine); D000493:Allopurinol; D007372:Interferons; D003577:Cytochrome P-450 Enzyme System; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase