Cytochrome P450 activity and distribution in the human colon mucosa.
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 km ten-fold 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 mumol/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.
Stralka
D J
DJ
Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston 77225.
Strobel
H W
HW
D019813:1,2-Dimethylhydrazine; D000328:Adult; D000588:Amines / Q000494:pharmacology; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D003106:Colon / Q000201:enzymology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004127:Dimethylhydrazines / Q000493:pharmacokinetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology*; D007700:Kinetics; D008297:Male; D008763:Methylhydrazines / Q000493:pharmacokinetics*; D008797:Metyrapone / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D008875:Middle Aged; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010084:Oxidation-Reduction; D011725:Pyridines / Q000494:pharmacology; D012016:Reference Values
D000588:Amines; D002273:Carcinogens; D004127:Dimethylhydrazines; D008763:Methylhydrazines; D011725:Pyridines; C013109:metapyrone; D003577:Cytochrome P-450 Enzyme System; D009247:NADH, NADPH Oxidoreductases; D019813:1,2-Dimethylhydrazine; C008699:octylamine; D008797:Metyrapone