INHIBITION OF HUMAN CYTOCHROME P450-CATALYZED OXIDATIONS OF XENOBIOTICS AND PROCARCINOGENS BY SYNTHETIC ORGANOSELENIUM COMPOUNDS

The effects of synthetic chemopreventive organoselenium compounds 1,2- , 1,3-, and 1,4-phenylenebis(methylene)selenocyanate (o-, m-, and p-XS C, respectively), benzyl selenocyanate (BSC), and dibenzyl diselenide (DDS) and inorganic sodium selenite on the oxidation of xenobiotics an d procarcinogens by human cytochrome p450 (P450 or CYP) enzymes were d etermined in vitro. Spectral studies showed that BSC and three XSC com pounds (but not sodium selenite or DDS) induced type II difference spe ctrum when added to the suspension of liver microsomes isolated from b eta-naphthoflavone-treated rats, with m-XSC being the most potent in i nducing spectral interactions with P450 enzymes; m-XSC also produced a type II spectral change with human liver microsomes. o-, m-, and p-XS C inhibited 7-ethoxyresorufin O-deethylation catalyzed by human liver microsomes when added at concentrations below 1 mu M levels, but BSC a nd DDS were less effective. All of these compounds inhibited the oxida tion of model substrates for human P450s to varying extents. We studie d the effects of these compounds on the activation of procarcinogens b y recombinant human CYP1A1, 1A2, and 1B1 enzymes using Salmonella typh imurium NM2009 tester strain for the detection of DNA damage. The thre e 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-dimethyli midazo[4,5-f]quinoline, and 2-aminoanthracene, catalyzed by CYP1A1, 1A 2, and 1B1, respectively. The potency of inhibition of m-XSC on CYP1B1 -dependent activation of 2-aminoanthracene was compatible to those of alpha-naphthoflavone. These inhibitory actions my, in part, account fo r the mechanisms responsible for cancer prevention by organoselenium c ompounds in laboratory animals.