Increased oxidation of a chemical carcinogen, benzo(a)pyrene, by colon tissue biopsy specimens from patients with ulcerative colitis.

Colonic biopsy specimens from patients with ulcerative colitis and normal subjects were studied for the ability to metabolize an environmental carcinogen, benzo(a)pyrene. Approximately 73% of 30 colonic biopsy specimens from 7 ulcerative colitis patients could metabolize benzo(a)pyrene to oxidized products, with an average production of 11.6 nmol/mg biopsy protein. In contrast, 39% of 23 biopsy specimens from 5 normal persons showed metabolic activity, with an average of 2.79 nmol benzo(a)pyrene metabolites/mg biopsy protein. Thus, benzo(a)pyrene oxidation activity in colonic tissue from colitis patients was, on the average, fourfold greater than that in normal subjects. This elevated metabolic activity appeared to be unrelated to the state of inflammation in the biopsy section. There was a tendency toward increased metabolic activity in the distal colon. Although there is no evidence that benzo(a)pyrene itself is "the colon carcinogen," this chemical belongs to a broad class of environmental carcinogens, the polycyclic aromatic hydrocarbons. Our findings suggest that the colonic mucosa of patients with ulcerative colitis has a greater ability than that of normal subjects to oxidize such chemicals possibly to electrophiles with higher mutagenic potential.

Enzymatic methylation of microsomal metabolites of benzo(a)pyrene.

These studies suggest that the microsomal metabolism of benzo(a)pyrene (BP) produces metabolites which can be methylated by the catechol-o-methyltransferase (COMT)/S-adenosylmethionine (SAM) enzyme/donor combination. Induced microsomes converted 12 to 15% of substrate BP to polar products. Approximately 0.06% of substrate BP was recovered as COMT/SAM-reactive substances. In tests for specificity, COMT/SAM was found to react with catechols, but not with dihydrodiols, quinones, a phenol, an epoxide, or 1,4-hydroquinone. Organic extracts of COMT/[14C]SAM incubations with BP were fractionated by high-performance liquid chromatography. The appearance of radiolabeled chromatographic bands required the presence of substrate BP, microsomes, and COMT/[14C]SAM. When the Ames mutagenesis assay was supplemented with COMT/SAM, a 36% reduction was observed in the number of revertant colonies induced by the microsomal oxidation of BP. In contrast, the mutagenic properties of 2-aminofluorene were not affected by COMT/SAM. These observations indicate that COMT/SAM does not generally inhibit mixed-function oxidase activity but rather reacts with substances which are activated by ring oxygenations.