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Fatty Acid-stimulated Oxidation of Methylazoxymethanol by Rat Colonic Mucosa¹

Department of Medicine, Veterans Administration Medical Center, Pittsburgh, Pennsylvania 15240

The present study examined fatty acid-initiated metabolism of methylazoxymethanol (MAM) to formaldehyde (HCHO) by the 10,000 x g soluble fraction of rat colonic mucosa, and the role of prostaglandin synthase and lipoxygenase activities in mediating this process. Incubation of MAM with soluble fractions of rat colonic mucosa, in the absence of arachidonate, resulted in significant HCHO production compared to that observed in buffer alone or with the heated tissue fractions. Addition of arachidonate (100 µM), linoleate (100 µM), or arachidonate hydroperoxide, but not palmitate, increased HCHO formation by 50%. Indomethacin (25 to 100 µM) suppressed basal and arachidonate-stimulated HCHO production by 25 to 50%. However, indomethacin did not influence linoleate or arachidonate hydroperoxide-induced increases in HCHO. These data suggested a peroxidative mechanism for MAM oxidation, that was mediated in part by arachidonate metabolism via the prostaglandin synthase system. 5,8,11,14-Eicosatetraynoic acid (25 to 500 µM) suppressed HCHO production by 30 to 80% in the absence of fatty acids, and abolished stimulation by arachidonate or linoleate, but not by arachidonate hydroperoxide. MAM was also oxidized by an NAD⁺-dependent dehydrogenase, as evidenced by MAM-mediated NAD reduction in 10,000 x g soluble fractions of rat colonic mucosa. On a molar basis, the ability of the soluble fraction of rat colonic mucosa to oxidize MAM by the NAD⁺-dependent dehydrogenase pathway and the fatty acid-stimulated pathway were similar. However, NADPH did not stimulate HCHO formation by MAM. Moreover, 7,8-naphthoflavone; 2-diethylaminoethyl-2,2-diphenylvalerate; and methimazole, inhibitors of mixedfunction oxidase activity, did not suppress HCHO formation, implying that MAM was not metabolized by the colonic mixedfunction oxidase activity. MAM metabolism to HCHO was 3 to 4 times greater by soluble fractions of superficial epithelial cells isolated from rat colon compared to those of the isolated proliferative epithelial cell pool. The results are consistent with a role for both the prostaglandin synthase and lipoxygenase systems of colonic mucosa in the oxidative metabolism of MAM. Enhanced oxidation of MAM by superficial cells of colonic epithelium which are preparing to slough may serve to protect the colon against the carcinogenic effect of this drug.

¹ This work was supported by USPHS Grant CA 31680 from the National Cancer Institute through the Large Bowel Cancer Project.

² To whom requests for reprints should be addressed, at the VA Medical Center, University Drive C., Pittsburgh, PA 15240.

Received 2/ 3/84. Accepted 12/ 7/84.

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