Cytochrome P450 activity and distribution in the human colon mucosa

Abstract

Enzymatic activity associated with the mixed-function oxidase system was determined in microsomes prepared from the mucosal cells extracted from normal human colons. A high activity toward nitrogen oxidation reactions was observed. 1,2-Dimethylhydrazine, a colon-specific carcinogen, was metabolized at a higher rate in vitro by human colon microsomes as compared with the rat, and exhibited a k_m tenfold lower, 1.03 mmol/l versus 9.68 mmol/l, respectively. This activity was inhibited by classic cytochrome P450 inhibitors; 70% inhibition was achieved using 70 mmol/l metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone), 20 mmol/l; SKF-525A (diethylaminoethyl-2,-2-diphenylvalerate HCl), or 350 μmol/l n-octylamine. These data suggest the presence of a stable, active mixed-function oxidase system in the human colon mucosa which has a preferential activity toward nitrogenous compounds and provides a mechanism for the activation of carcinogens. Its distribution in the colon appears to parallel the reported incidence of human colonic carcinomas.