The effects of administration of phenobarbital and methylcholanthrene to rats on the substrate-induced spectral changes of liver microsomal P-450 were investigated. The administration of phenobarbital increased the content of P-450 and the magnitudes of hexobarbital, aminopyrine, aniline and zoxazolamine-induced spectral changes and oxidation of the drugs by liver microsomes. The activities to hydroxylate hexobarbital and aniline and to N-demethylate aminopyrine per the magnitudes of the substrate-induced spectral changes were decreased in microsomes isolated from phenobarbital treated rats, whereas the zoxazolamine hydroxylation activity per the magnitude of the spectral change was increased. The administration of methylcholanthrene to male rats increased the content of P-450, whereas the magnitudes of spectral changes induced by hexobarbital and aminopyrine were decreased in accordance with the decreases in the activities of hexobarbital hydroxylation and aminopyrine N-demethylation. In contrast, the magnitudes of aniline and zoxazolamine-induced spectral changes and aniline and zoxazolamine hydroxylations were markedly increased in methylcholanthrene-treated rats. These results suggest that the difference in the effects of methylcholanthrene is not due to the difference in the type of spectral change, but it may be related to the difference in the degree of androgen dependence in the magnitude of the spectral changes. On the other hand, the administration of methylcholanthrene to female rats decreased the magnitudes of hexobarbital and aminopyrine-induced spectral changes, but the metabolisms of those drugs were not significantly affected. Marked alteration in the shape of the difference spectra induced by hexobarbital, aminopyrine and zoxazolamine was observed in microsomes isolated from methylcholanthrene treated rats. The administration of phenobarbital did not alter the Km and K, (spectral dissociation constant) values for the hexobarbital hydroxylation and spectral change, but increased the Km value for aniline hydroxylation. The Km value for the aniline hydroxylation was markedly increased in microsomes isolated from methylcholanthrene-treated rats, in contrast the K3 value for anilineinduced spectral changes was decreased. On the other hand, the Km and K3 values for the hexobarbital hydroxylation and spectral change were not affected by methyl-cholanthrene treatment. The mechanism of methylcholanthrene-induced alterations of the spectral changes and drug oxidations is discussed.
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Kato et al. (1970) studied this question.