Extrahepatic Microsomal Forms: Gastrointestinal Cytochromes P450, Assessment and Evaluation

Abstract

The cytochrome P450 dependent drug metabolism system (Lu and West 1978; Nebert and Gonzales 1987) has been shown to exist in many mammalian tissues, including the gastrointestinal tract. The hydroxylation of benzo[a]pyrene has been observed to be induced in the esophagus, forestomach, duodenum, small intestine, cecum and colon of animals treated with 1,2-benzanthracene, a well-known inducer of cytochromes P450 (Wattenberg et al. 1962; Wattenberg and Leong 1962). The treatment of animals with benzo[a]pyrene has been reported to induce both an increase in arylhydrocarbon hydroxylase activity in the forestomach and the occurrence of tumors in the forestomach (Triolo et al. 1977). The small intestine has been shown to catalyze the O-dealkylation of phenacetin (Pantuck et al. 1975) as well as 7-ethoxycoumarin. A major step forward in the study of drug and carcinogen metabolism was made by Stohs and his colleagues, who first succeeded in preparing intestinal mucosa microsomes with stable cytochrome P450 and catalytic activity (Stohs et al. 1976). These workers showed that intestinal cytochrome P450 content and cytochrome P450 reductase, as well as benzo[a]pyrene hydroxylation rates, were inducible by treatment with inducers. Ichihara et al. (1979) were the first to solubilize and partially purify a cytochrome P450 isoform from the small intestine.