INHIBITION OF 2-NITROPROPANE-INDUCED RAT-LIVER DNA AND RNA DAMAGE BY BENZYL SELENOCYANATE

We observed that pretreatment of male F344 rats with benzyl selenocyan ate, a versatile organoselenium chemopreventive agent in several anima l model systems, decreases the levels of DNA and RNA modifications pro duced in the liver by the hepatocarcinogen 2-nitropropane, To clarify the mechanisms involved, we pretreated male F344 rats with either benz yl selenocyanate, its sulfur analog benzyl thiocyanate, phenobarbital or cobalt protoporphyrin IX; the latter is a depletor of P450, We then determined (1) the ability of liver microsomes to denitrify 2-nitropr opane, (2) effects on 2-nitropropane-induced liver DNA and RNA modific ations and (3) amount of nitrate excreted in rat urine following admin istration of the carcinogen, Pretreatment with benzyl selenocyanate or phenobarbital increased the denitrification activity of liver microso mes by 217 and 765%, respectively, increased liver P4502B1 by 31- and 435-fold, respectively, decreased the levels of 2-nitropropane-induced modifications in liver DNA (29-70% and 17-30%, respectively) and RNA (67-85% and 30-50%, respectively), and increased the 24-h urinary excr etion of nitrate by 157 and 209%, respectively, Pretreatment with benz yl thiocyanate had no significant effect on any of these parameters, P retreatment with cobalt protoporphyrin IX decreased liver P4502B1 by 8 7%, decreased the denitrification activity of liver microsomes by 76%, decreased the 24 h urinary excretion of nitrate by 88.5%, but increas ed the extent of 2-nitropropane-induced liver nucleic acid modificatio ns by 17-67%, These results indicate that the metabolic sequence from 2-nitropropane to the reactive species causing DNA and RNA modificatio ns does not involve the removal of the nitro group, Moreover, they sug gest that benzyl selenocyanate inhibits 2-NP-induced liver nucleic aci d modifications in part by increasing its detoxication through inducti on of denitrification, although it is evident that other mechanisms mu st also be involved.