Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate

We observed that pretreatment of male F344 rats with benzyl selenocyanate,a versatile organoselenium chemopreventive agent in several animal modelsystems, decreases the levels of DNA and RNA modifications produced in theliver by the hepatocarcinogen 2- nitropropane. To clarify the mechanismsinvolved, we pretreated male F344 rats with either benzyl selenocyanate,its sulfur analog benzyl thiocyanate, phenobarbital or cobaltprotoporphyrin IX; the latter is a depletor of P450. We then determined (1)the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on2-nitropropane- induced liver DNA and RNA modifications and (3) amount ofnitrate excreted in rat urine following administration of the carcinogen.Pretreatment with benzyl selenocyanate or phenobarbital increased thedenitrification activity of liver microsomes by 217 and 765%, respectively,increased liver P4502B1 by 31- and 435-fold, respectively, decreased thelevels of 2-nitropropane-induced modifications in liver DNA (29-70% and17-30%, respectively) and RNA (67-85% and 30-50%, respectively), andincreased the 24-h urinary excretion of nitrate by 157 and 209%,respectively. Pretreatment with benzyl thiocyanate had no significanteffect on any of these parameters. Pretreatment with cobalt protoporphyrinIX decreased liver P4502B 1 by 87%, decreased the denitrification activityof liver microsomes by 76%, decreased the 24 h urinary excretion of nitrateby 88.5%, but increased the extent of 2-nitropropane-induced liver nucleicacid modifications by 17-67%. These results indicate that the metabolicsequence from 2-nitropropane to the reactive species causing DNA and RNAmodifications does not involve the removal of the nitro group. Moreover,they suggest that benzyl selenocyanate inhibits 2-NP-induced liver nucleicacid modifications in part by increasing its detoxication through inductionof denitrification, although it is evident that other mechanisms must alsobe involved.