Manganese-mediated increase in the rat brain mitochondrial cytochrome P-450 and drug metabolism activity: susceptibility of the striatum.

The present study describes the high degree of sensitivity of the mitochondrial fraction of the striatum to Mn++-mediated perturbations in mixed-function oxidase activity. This study also defines the brain mitochondrial cytochrome P-450 subject to increase by Mn++. In the striatum of Mn++-treated animals (7 days) hydroxylation of benzo(a)pyrene and D-amphetamine was significantly increased in both the mitochondrial and the microsomal fractions. The effects were more pronounced in the mitochondrial fraction where hydroxylation activities were increased by 2- to 3-fold. SKF-525A (2-diethylaminoethyl-2,2-di-phenylvalerate hydrochloride) effectively inhibited NADH-dependent hydroxylation of both substrates by the mitochondrial fraction. In the Mn++-treated animals, significant increases in mitochondrial and microsomal cytochrome P-450 concentration were also noted. In the mitochondria, the hemoprotein concentration was increased by nearly 2.5-fold; in the microsomes the concentration of the cytochrome was increased by about 1.6-fold. Mn++ appeared to selectively increase cytochrome P-450 concentration since that of other cytochromes including the mitochondrial b, c1, c and a, and the microsomal cytochrome b5 was not increased. In addition, the activity of mitochondrial delta-aminolevulinate synthetase was not increased and that of the microsomal heme oxygenase was inhibited by Mn++ treatment. It is suggested that increases in the microsomal and the mitochondrial cytochrome P-450 may reflect intrinsic properties of cytochrome P-450 isozymes in these organelles, including their turnover rate, preferential utilization of heme and/or susceptibility to degradation. The possible relevance of the findings to Mn++ neurotoxicity of dopamine pathways is discussed.