Free radicals generated by xanthine oxidase-hypoxanthine damage adenylate cyclase and ATPase in gerbil cerebral cortex.
The generation of superoxide radicals from xanthine oxidase-hypoxanthine in a particulate fraction of gerbil cerebral cortex influenced the activity of the synaptic enzyme adenylate cyclase, as well as Mn2+- and Na+,K+-sensitive forms of ATPase. Low concentrations of xanthine oxidase actually elevated the sensitivity of adenylate cyclase to GTP, GTP + norepinephrine (NE), and forskolin but not significantly to Mn2+. Higher levels of xanthine oxidase elicited a marked inhibition of these responses. The stimulation of adenylate cyclase mechanisms requiring GTP (GTP, forskolin, and NE) was more susceptible than was Mn2+, suggesting that the guanine nucleotide stimulatory protein was more vulnerable to free radical attack than the catalytic site of adenylate cyclase. Superoxide dismutase (SOD), but not catalase, partially protected the forskolin-sensitive enzyme from the action of xanthine oxidase-hypoxanthine. A combination of SOD plus catalase preserved enzyme responses to forskolin. In comparison, additions of SOD plus mannitol or catalase plus flunarizine were less effective. The sensitivity of the particulate ATPase to Mn2+ was more labile to the consequence of superoxide formation than Na+, K+ -ATPase. In this regard the Ca2+,Mg2+ sensitivity of the enzyme was reduced only to a marginal extent. The findings might be analogous to in vivo data in which cerebral adenylate cyclase and Na+, K+-ATPase are damaged following postischemic reperfusion in gerbils, a process thought to be mediated by free radicals.
Palmer
G C
GC
Pennwalt Corporation, Pharmaceutical Division, Rochester, New York 14623.
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D005576:Colforsin / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D005609:Free Radicals; D005849:Gerbillinae; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000633:toxicity*; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014969:Xanthine Oxidase / Q000633:toxicity*
D005609:Free Radicals; D007042:Hypoxanthines; D013481:Superoxides; D005576:Colforsin; D019271:Hypoxanthine; D008345:Manganese; D014969:Xanthine Oxidase; D000251:Adenosine Triphosphatases; D000262:Adenylyl Cyclases; D008274:Magnesium