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Inhibition of Human Cytochrome P450-catalyzed Oxidations of Xenobiotics and Procarcinogens by Synthetic Organoselenium Compounds¹

Osaka Prefectural Institute of Public Health, Osaka 537, Japan [T. S., H. Y.]; Department of Environmental Health Sciences, Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595 [K. E., P. U.]; Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205 [T. R. S.]; and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 [F. P. G.]

The effects of synthetic chemopreventive organoselenium compounds 1,2-, 1,3-, and 1,4-phenylenebis(methylene)selenocyanate (o-, m-, and p-XSC, respectively), benzyl selenocyanate (BSC), and dibenzyl diselenide (DDS) and inorganic sodium selenite on the oxidation of xenobiotics and procarcinogens by human cytochrome P450 (P450 or CYP) enzymes were determined in vitro. Spectral studies showed that BSC and three XSC compounds (but not sodium selenite or DDS) induced type II difference spectrum when added to the suspension of liver microsomes isolated from ß-naphthoflavone-treated rats, with m-XSC being the most potent in inducing spectral interactions with P450 enzymes; m-XSC also produced a type II spectral change with human liver microsomes. o-, m-, and p-XSC inhibited 7-ethoxyresorufin O-deethylation catalyzed by human liver microsomes when added at concentrations below 1 µM levels, but BSC and DDS were less effective. All of these compounds inhibited the oxidation of model substrates for human P450s to varying extents. We studied the effects of these compounds on the activation of procarcinogens by recombinant human CYP1A1, 1A2, and 1B1 enzymes using Salmonella typhimurium NM2009 tester strain for the detection of DNA damage. The three XSCs were found to be very potent inhibitors of metabolic activation of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 2-amino-3,5-dimethylimidazo[4,5-f]quinoline, and 2-aminoanthracene, catalyzed by CYP1A1, 1A2, and 1B1, respectively. The potency of inhibition of m-XSC on CYP1B1-dependent activation of 2-aminoanthracene was compatible to those of -naphthoflavone. These inhibitory actions may, in part, account for the mechanisms responsible for cancer prevention by organoselenium compounds in laboratory animals.

¹ This work was supported in part by Grants from the Ministry of Education, Science, Sports and Culture of Japan, the Ministry of Health and Welfare of Japan, the Developmental and Creative Studies from Osaka Prefectural Government, and by USPHS Grants CA46589, CA70792, CA44353, ES00267, and ES06071.

² To whom requests for reprints should be addressed, at Osaka Prefectural Institute of Public Health; 3-69 Nakamichi 1-chome, Higashinari-ku, Osaka 537, Japan. Fax: 81-6-972-2393; E-mail: shimada@iph.pref.osaka.jp.

Received 4/10/97. Accepted 9/ 8/97.

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