PROTECTION CONFERRED BY SELENIUM DEFICIENCY AGAINST AFLATOXIN B-1 IN THE RAT IS ASSOCIATED WITH THE HEPATIC EXPRESSION OF AN ALDO-KETO REDUCTASE AND A GLUTATHIONE-S-TRANSFERASE SUBUNIT THAT METABOLIZE THE MYCOTOXIN

Fischer 344 rats fed on a diet that is deficient in selenium are more resistant to the hepatocarcinogen aflatoxin B-1 (AFB(1)) than those fe d on a selenium-sufficient diet, Hepatic cytosol from either selenium- deficient Fischer 344 rats or Hooded Lister rats possesses a marked in crease in both reductase activity toward AFB(1)-dialdehyde and glutath ione S-transferase (GST) activity toward AFB(1)-8,9-epoxide than hepat ic cytosol from selenium-sufficient rats, The elevation in hepatic AFB (1)-aldehyde reductase (AFAR) activity in selenium-deficient animals i s accompanied hy an increase of 11- and 15-fold in the levels of AFAR protein in liver cytosol from Fischer 344 and Hooded Lister rats, resp ectively, The amount of AFAR protein in selenium-sufficient and -defic ient Fischer rats was modulated by treatment with N-acetylcysteine; th is antioxidant reduced basal expression of AFAR but did not modulate t he relative overexpression of AFAR during selenium deficiency, The enh anced capacity to conjugate glutathione with AFB(1)-8,9-epoxide in sel enium-deficient Livers from Fischer 344 and Hooded Lister rats is asso ciated with a 5- and 7-fold increase, respectively, in the hepatic lev els of the AFB(1)-metabolizing alpha-class GSTA5 subunit, The elevated levels of AFAR and GSTA5 protein in the selenium-deficient animals co incided with increases in the steady-state levels of their mRNAs, In s elenium-deficient Fischer 344 rats, AFAR and GSTA5 were both found to be expressed throughout the centrilobular and midzonal areas of the li ver lobule but were essentially absent from periportal hepatocytes. Th e effect of selenium insufficiency is pleiotropic, and it was also not ed that the theta-class GSTT1 is overexpressed 3-and 10-fold in livers of selenium-deficient Hooded Lister and Fischer 344 rats, Inasmuch as GSTT1 is responsible for the metabolic activation of dihaloalkanes, s elenium deficiency mag increase the susceptibility of rats to mutagens such as dichloromethane.