CLONING OF CDNAS FROM FETAL-RAT LIVER ENCODING GLUTATHIONE-S-TRANSFERASE YC POLYPEPTIDES - THE YC(2) SUBUNIT IS EXPRESSED IN ADULT-RAT LIVER RESISTANT TO THE HEPATOCARCINOGEN AFLATOXIN B-1

Fetal rat liver possesses substantial levels of glutathione S-transfer ase (GST) activity toward aflatoxin B-1-8,9-epoxide. The enzyme respon sible for this activity is an Alpha-class GST heterodimer comprising Y c(1) and Yc(2) subunits. The cDNAs encoding these polypeptides have be en cloned and shown to share approximately 91% identity over 920 base pairs, extending from nucleotide -23 to the AATAAA polyadenylation sig nal. GST Yc(2)Yc(2) expressed in Escherichia coli was found to exhibit 150-fold greater activity toward aflatoxin B-1-8,9-epoxide than GST Y c(1)Yc(1). Comparison between the structures of Alpha-class GST sugges ts that tyrosine at residue 108 and/or aspartate at residue 208 is res ponsible for the high aflatoxin B-1 detoxication capacity of Yc(2). Im munoblotting and enzyme assays have shown that liver from adult female rats contains about 10-fold greater levels of Yc(2) than is found in liver from adult male rats. This sex-specific expression of Yc(2), in adult rat liver may contribute to the relative insensitivity of female rats to aflatoxin B-1. Dietary administration of oltipraz, a syntheti c antioxidant which protects against aflatoxin-hepatocarcinogenesis, s erves as an inducer of GST Yc(2).