Molecular Pharmacology, Vol 8, 327-338, Copyright © 1972 by the American Society for Pharmacology and Experimental Therapeutics

Hepatic Organelle Interaction

I. Spectral Investigation During Drug Biotransformation

¹ Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510

A technique which permits the measurement of levels of mitochondrial and endoplasmic reticulum pigments in the hepatocyte, the examination of changes in the oxidation-reduction states of these pigments, and the study of interactons between the mitochondrial and endoplasmic reticulum electron transport chains is described. The content of cytochrome P-450 was about 30 nmoles/g of liver, wet weight. Based on the microsomal concentration of cytochrome P-450, the microsomal protein content ranged from 50 to 70 mg/g of liver. The total mitochondrial pigment concentration was 83 nmoles/g of liver, wet weight, and 1.16 nmoles/mg of mitochondrial protein. Based on these figures there were about 75 mg of mitochondrial protein per gram of liver. The rate of reduction of cytochrome P-450 in liver slices was also measured; the endogenous rate of reduction was 1.5-3.0 nmoles/g of liver per minute, and it increased to 4.5 nmoles/g/min in the presence of NADPH. The addition of 8 mM aminopyrine doubled the rate of reduction of cytochrome P-450 to 5.0-6.0 nmoles. When a Krebs cycle intermediate such as succinate was added in the presence of aminopyrine, a further doubling of the rate of reduction of cytochrome P-450 occurred (9.0-10.0 nmoles/g of liver per minute). The presence of succinate in the medium containing both aminopyrine and NADPH increased the P-450 reductase activity synergistically to 23 nmoles/g of liver per minute. These data indicate that the mitochondria may be a site of cellular control of drug biotransformation in the endoplasmic reticulum.

Note:
ACKNOWLEDGMENT The authors express their thanks to Dr. Joan Higgins of the Department of Anatomy, Yale University, for the interpretation of the electron micrographs.

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