Regulation of heme and drug metabolism activities in the brain by manganese.
A novel effect of metal ions in the brain is described. Mn was found to alter heme metabolism and the cytochrome P-450-dependent mixed-function oxidase activities in rat brain. A more than 2-fold increase in benzo(alpha)pyrene hydroxylase and 7-ethoxycoumarin deethylase activities were observed in the brain of rats treated for 7 days with Mn. The increases were regionally distributed; the highest elevations were observed in the hippocampus, pons and the caudate putamen. Moreover, in rats treated with Mn for 1 or 7 days a marked depression in the activity of the mitochondrial ALA synthetase was observed. The activity of the microsomal heme oxygenase was also inhibited at 7 days, but not 1 day, after Mn treatment. These inhibitions were reflected in an initial decrease, followed by a rebound return to normal, in the concentration of cytochrome P-450 in the brain. Mn was ineffective in vitro in altering heme and drug metabolism activities. It is suggested that Mn-mediated alterations in heme metabolic activities promote changes in the composition of cytochrome P-450 species in the brain microsomal fractions, such that the relative concentrations of the molecular species which catalyse aryl hydrocarbon hydroxylase activity become selectively increased.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D008297:Male; D008345:Manganese / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D006418:Heme; D008345:Manganese; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D001579:Benzopyrene Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase