Pathobiodynamics: Effect of extrahepatic inflammation on calcium transport and drug metabolism by rat liver mitochondria in vitro

The effects of inflammation induced by the inoculation of rats with either Freund's adjuvant or oleyl alcohol on calcium transport and hippurate formation by isolated liver mitochondria, and on the activities of several nonoxidative drug-metabolizing systems were investigated. Intact mitochondria isolated from the liver of inflamed rats exhibit (i) a greater sensitivity to the uncoupling action of Ca²⁺ as monitored by the Ca²⁺ stimulation of succinate oxidation, (ii) a decreased ability to retain accumulated Ca²⁺, (iii) a more rapid, and a greater, rate of Ca²⁺-induced osmotic swelling, and (iv) subnormal 4-aminobenzoate conjugation with glycine when this reaction is measured in the absence of exogenous Mg²⁺. The addition of Mg²⁺ to the assay medium overcame the inhibition of 4-aminobenzoate conjugation but did not abolish the differences between liver mitochondria from inflamed rats and those from normal control animals with respect to the uncoupling action of Ca²⁺ on respiration. No significant difference was observed in mitochondria from inflamed and control animals when a number of parameters of the mitochondrial energy-transducing systems were measured. No significant differences were found in the O-sulfation or N-acetylation of drugs by liver cytosol enzymes or in the pyrophosphatase activity of liver microsomes from normal and inflamed rats of the same sex. Liver microsomes from inflamed rats showed less O-glucuronidation activity than normal liver microsomes but the relative loss of this enzyme activity was of later onset and less magnitude than the rapid decline in microsomal drug-hydroxylating activities.