ARTICLE

ON THE MECHANISM OF DRUG HYDROXYLATION IN RAT LIVER MICROSOMES

Sten Orrenius ¹

¹ From the Department of Pathology at Sabbatsberg Hospital, Karolinska Institutet, and The Wenner-Gren Institute, University of Stockholm, Stockholm, Sweden

The TPNH- and O₂-dependent drug hydroxylation system of liver microsomes has been studied using normal rats and rats in which the drug-hydroxylating activity has been enhanced by repeated injections of phenobarbital. The oxidative demethylation of aminopyrine is employed as an assay. Optimal conditions for the assay with regard to the concentrations of TPNH and aminopyrine are established. TPN inhibits the reaction in a competitive manner, similarly to its effect on the microsomal TPNH-cytochrome c reductase. Drug hydroxylation, but not the "TPNH oxidase," TPNH-cytochrome c, -2,6-dichlorophenolindophenol, or -neotetrazolium reductase reaction, or the TPNH-dependent lipid peroxidation, is blocked by carbon monoxide. Microsomes from phenobarbital-treated rats exhibit increased activities of the various TPNH-linked reductase reactions, parallel to the increased drug hydroxylation activity, whereas the "TPNH oxidase" activity does not change appreciably. Measurements with microsomes from drug-treated animals reveal a 1:1:1 stoichiometry of aminopyrine-dependent oxygen uptake, TPNH oxidation, and formaldehyde formation. Attempts to solubilize the drug-hydroxylating enzyme system are also presented. It is concluded that the drug-hydroxylating enzyme system involves the microsomal TPNH-cytochrome c reductase and CO-binding pigment, and a hypothetic reaction scheme accounting for the data presented is proposed.

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• Chedid, A., Nair, V. (1972). Diurnal Rhythm in Endoplasmic Reticulum of Rat Liver: Electron Microscopic Study. Science 175: 176-179 [Abstract]  
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• Lundkvist, U., Perlmann, P. (1966). Immunochemical Studies of Submicrosomal Membranes from Liver of Normal and Phenobarbital-Treated Rats. Science 152: 780-782 [Abstract]  

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