N-nitrosodimethylamine induced changes in the activities of carcinogen-metabolizing enzymes in the liver of male mice: role of glutathione and gossypol as antioxidants

Abstract

The importance of nutrition in protecting living organisms from the toxic effects of environmental carcinogens
has attracted the attention of many researchers. In order to exert their toxic and/or carcinogenic effects, most
carcinogens need to be activated primarily by phase I drug-metabolizing enzymes including; cytochrome P450,
cytochrome b5, arylhydrocarbon hydroxylase (AHH), N-nitroso-dimethylamine N- demethylase I (NDMA-N-dI),
NADPH- cytochrome c reductase and the expression of cytochrome P450 2E1. Changes in the activity of these
enzymes were determined in livers of male mice pretreated with either glutathione (GSH) or gossypol as
antioxidants, for seven consecutive days before administration of NDMNA as single dose for two hours before
decapitation of mice. The total hepatic content of cytochrome P450 and AHH activity were induced, whereas the
activity of NDMA-N-dI and expression of cytochrome P450 2E1 were reduced after treatment of mice with NDMA
as a single dose. On the other hand, preteatments of mice with either gossypol or GSH for seven consecutive
days decreased the total cytochrome P450 content as well as AHH activity whereas the activity of NDMA-N-dI
and the expression of cytochrome P450 2E1 increased. Treatment of mice with NDMA only induced the total
hepatic content of cytochrome P450 and AHH activity. Interestingly pretreatment of mice with GSH for seven
consecutive days before injection of NDMA was found to restore the induced cytochrome P450 and AHH
activity caused by NDMA to their normal levels. However, pretreatment of mice with gossypol prior to
administration of NDMA did not restore such activities to their normal levels. Treatment of mice with either GSH
or gossypol induced the expression of cytochrome P450 2E1. Interestingly, gossypol/NDMA treated mice
restored the induced cytochrome P450 2E1 expression, caused by gossypol, to its normal level. However,
GSH/NDMA-treated mice did not restore the induced level of cytochrome P450 2E1 caused by GSH, to its
normal level. It is concluded that, pretreatment of mice with GSH and gossypol prior to administration of NDMA
induced the expression of cytochrome P450 2E1. Therefore, GSH and gossypol, could induce the toxicity
and/or carcinogenicity of N-nitrosamines whereas they might protect the liver and probably other organs from
the toxic and carcinogenic effects of other carcinogens such as polycyclic aromatic hydrocarbons, e.g.
benzo[a]pyrene, through inhibition of total cytochrome P450 content and AHH activity.