THEOPHYLLINE METABOLISM BY RAT-LIVER MICROSOMAL SYSTEM

  • 1 January 1976
    • journal article
    • research article
    • Vol. 196  (1) , 213-225
Abstract
The metabolism of 8- 14C-theophylline (14C-Theo) was investigated in vivo and in vitro in the rat. In vivo 14C-Theo at an initial blood concentration of 10 .mu.M was metabolized to at least 2 different metabolites, 1,3-dimethyl uric acid and 1-methyl uric acid. The biological half-life of the 8-14C-Theo (6 .+-. 1.5 h) was determined from the urinary excretion of radioactivity. Ten days of oral pretreatment of rats with theophylline resulted in a faster rate of metabolism of both 14C-Theo and zoxazolamine. In vitro metabolism of 14C-Theo was investigated in order to identify the enzyme(s) responsible for theophylline metabolism. A tissue survey utilizing tissue slices demonstrated that the metabolism is localized only in the liver since slices of heart, lung, intestine, brain, adrenals, kidney or spleen did not metabolize 14C-Theo. 14C-Theo metabolism in the liver was localized in the subcellular fraction of microsomes and not in the mitchondria or cytosol. 14C-Theo metabolism by liver slices or liver microsomes was inhibited by typical liver microsomal inhibitors such as 2-diethylaminoethyl-2,2-diphenylvalerate (SKF 525-A) and 3-methyl-4-methylaminozobenzene. 14C-Theo metabolism in liver slices was increased by the liver microsomal-inducing agents, phenobarbital and 3-methylcholanthrene. 3-Methylcholanthrene increased 14C-Theo metabolism by the liver microsomal fraction. One metabolite 1-methylxanthine, generated by the microsomal system, is a substrate for xanthine oxidase, and its conversion to 1-methyl uric acid by xanthine oxidase was blocked by allopurinol. 14C-Theo per se was shown not to be a substrate for liver xanthine oxidase or aldehyde oxidase. Theo per se is metabolized by the liver microsomal system and not by liver xanthine oxidase or aldehyde oxidase.