Cloning of cDNAs from fetal rat liver encoding glutathione S-transferase Yc polypeptides. The Yc2 subunit is expressed in adult rat liver resistant to the hepatocarcinogen aflatoxin B1.
Fetal rat liver possesses substantial levels of glutathione S-transferase (GST) activity toward aflatoxin B1-8,9-epoxide. The enzyme responsible for this activity is an Alpha-class GST heterodimer comprising Yc1 and Yc2 subunits. The cDNAs encoding these polypeptides have been cloned and shown to share approximately 91% identity over 920 base pairs, extending from nucleotide -23 to the AATAAA polyadenylation signal. GST Yc2Yc2 expressed in Escherichia coli was found to exhibit 150-fold greater activity toward aflatoxin B1-8,9-epoxide than GST Yc1Yc1. Comparison between the structures of Alpha-class GST suggests that tyrosine at residue 108 and/or aspartate at residue 208 is responsible for the high aflatoxin B1 detoxication capacity of Yc2. Immunoblotting and enzyme assays have shown that liver from adult female rats contains about 10-fold greater levels of Yc2 than is found in liver from adult male rats. This sex-specific expression of Yc2 in adult rat liver may contribute to the relative insensitivity of female rats to aflatoxin B1. Dietary administration of oltipraz, a synthetic antioxidant which protects against aflatoxin-hepatocarcinogenesis, serves as an inducer of GST Yc2.
Hayes
J D
JD
Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Scotland, United Kingdom.
Nguyen
T
T
Judah
D J
DJ
Petersson
D G
DG
Neal
G E
GE
D016604:Aflatoxin B1 / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004351:Drug Resistance; D004790:Enzyme Induction; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000196:embryology / Q000201:enzymology*; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D017386:Sequence Homology, Amino Acid
D002273:Carcinogens; D018076:DNA, Complementary; D010446:Peptide Fragments; C006426:aflatoxin B1-2,3-oxide; D016604:Aflatoxin B1; D005982:Glutathione Transferase