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Protection Conferred by Selenium Deficiency against Aflatoxin B₁ in the Rat Is Associated with the Hepatic Expression of an Aldo-Keto Reductase and a Glutathione S-Transferase Subunit That Metabolize the Mycotoxin¹

Biomedical Research Centre [R. M., E. M. E., J. D. H.], and Department of Obstetrics and Gynaecology [E. M. E.], Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland; Division of Biochemical Sciences, Rowett Research Institute, Bucksburn, Aberdeen AB2 9SB, Scotland [J. R. A.], and Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, England [G. E. N., D. J. J., M. M. M.], United Kingdom

Fischer 344 rats fed on a diet that is deficient in selenium are more resistant to the hepatocarcinogen aflatoxin B₁ (AFB₁) than those fed on a selenium-sufficient diet. Hepatic cytosol from either selenium-deficient Fischer 344 rats or Hooded Lister rats possesses a marked increase in both reductase activity toward AFB₁-dialdehyde and glutathione S-transferase (GST) activity toward AFB₁-8,9-epoxide than hepatic cytosol from selenium-sufficient rats. The elevation in hepatic AFB₁-aldehyde reductase (AFAR) activity in selenium-deficient animals is accompanied by an increase of 11- and 15-fold in the levels of AFAR protein in liver cytosol from Fischer 344 and Hooded Lister rats, respectively. The amount of AFAR protein in selenium-sufficient and -deficient Fischer rats was modulated by treatment with N-acetylcysteine; this antioxidant reduced basal expression of AFAR but did not modulate the relative overexpression of AFAR during selenium deficiency. The enhanced capacity to conjugate glutathione with AFB₁-8,9-epoxide in selenium-deficient livers from Fischer 344 and Hooded Lister rats is associated with a 5- and 7-fold increase, respectively, in the hepatic levels of the AFB₁-metabolizing -class GSTA5 subunit. The elevated levels of AFAR and GSTA5 protein in the selenium-deficient animals coincided with increases in the steady-state levels of their mRNAs. In selenium-deficient Fischer 344 rats, AFAR and GSTA5 were both found to be expressed throughout the centrilobular and midzonal areas of the liver lobule but were essentially absent from periportal hepatocytes. The effect of selenium insufficiency is pleiotropic, and it was also noted that the -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, selenium deficiency may increase the susceptibility of rats to mutagens such as dichloromethane.

¹ Supported by Grants G9027099SA and G9322073PA from the Medical Research Council and Equipment Grant K/CSO/2/20/3/7 from the Scottish Office Home and Health Department to purchase the centrifugal analyzer. E. M. E. is a Beit Memorial Research Fellow. J. R. A. is supported by Scottish Office Agriculture, Environment and Fisheries Department.

² These authors contributed equally to this work.

³ To whom requests for reprints should be addressed, at Biomedical Research Centre, Ninewells Hospital and Medical School, Level 5, Dundee DD1 9SY, Scotland.

Received 5/ 8/97. Accepted 8/ 1/97.

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