Es. Fiala et al., INHIBITION OF 2-NITROPROPANE-INDUCED RAT-LIVER DNA AND RNA DAMAGE BY BENZYL SELENOCYANATE, Carcinogenesis, 18(9), 1997, pp. 1809-1815
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.