Molecular Pharmacology, Vol 6, 221-230, Copyright © 1970 by the American Society for Pharmacology and Experimental Therapeutics

Characteristics of Guinea Pig Liver and Adrenal Monooxygenase Systems

¹ Department of Biochemistry, University of Stockholm, Sweden

Liver and adrenal microsomes from the guinea pig were found to catalyze the oxidative demethylation of p-chloro-N-methylaniline and aminopyrine, ane the -oxidation of laurate. These activities were markedly higher in the liver than in the adrenals.

The level of cytochrome P-450 was higher in adrenal than in liver microsomes, whereas the rate of cytochrome P-450 reduction by NADPH was substantially lower in adrenal microsomes than in liver microsomes. This finding suggests that the reduction of cytochrome P-450 —rather than the amount of cytochrome P-450—may be the rate-determining step in the oxidative demethylation and -oxidation reactions.

Spectral changes induced by the addition of various compounds to liver and adrenal microsomes were examined. (a) Cortisol and cortisol 21-sodium succinate (cortisol succinate) were found to yield type I spectra with adrenal microsomes, but with liver microsomes these compounds yielded either a weak type I spectrum or no spectral changes; occasionally even a type II spectrum was evident. (b) Aminopyrine and hexobarbital gave type I spectra with liver microsomes and no spectral changes with adrenal microsomes. (c) p-Chloro-N-methylaniline gave a type II spectrum with both liver and adrenal microsomes. Despite the apparent inability of hexobarbital and aminopyrine to produce spectral changes in adrenal microsomes, these compounds diminished the magnitude of the type I spectrum produced by cortisol succinate and cortisol. It is proposed that the binding sites responsible for spectral changes and for metabolism are not necessarily identical, and that a given compound can bind at more than one site.

The effects of the compounds tested on the rates of NADPH-mediated reduction of cytochrome P-450 were different in liver and adrenal microsomes. However, the ability of a compound to enhance the rate of cytochrome P-450 reduction was found to be correlated with its capacity to induce a type I spectral change in microsomes from the respective tissues.

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ACKNOWLEDGMENTS The authors would like to thank Professor Lars Ernster for helpful discussions. The expert assistance of Mrs. Hjördis Thor and Miss Margareta Sparthan is gratefully acknowledged.

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