Human variability in hepatic glutathione S-transferase-mediated conjugation of aflatoxin B1-epoxide and other substrates.
Hepatic cytosolic fractions prepared from 14 human donors were analysed for glutathione S-transferase (GST) activity towards synthetic aflatoxin B1-8,9-epoxide (AFBO). In addition, GST-AFBO activity of pooled human liver cytosols was compared with rat, hamster, and mouse liver cytosol GST-AFBO activities. Consistent with previous studies, human liver cytosolic GSTs exhibited little activity towards AFBO. Hepatic GST-AFBO activities of rat, hamster, and mouse were 48-, 56-, and 312-fold greater, respectively, than observed for human liver using synthetic AFBO, and 70-, 465-, and 3545-fold greater, respectively, than observed for human liver using microsomally-generated AFBO. Furthermore, there was a 58-fold variation in hepatic GST-AFBO activities among the 14 human samples using synthetic AFBO as a substrate. Large interindividual variations were also observed with respect to GST activities towards bromosulfophthalein (BSP, 92-fold variation) and 3,4-dichloronitrobenzene (DCNB, 36-fold variation). Lesser interindividual variations were observed with respect to human liver GST activities towards benzo(a)pyrene-4,5-oxide (BaPO, 9-fold variation), 1-chloro-2,4-dinitrobenzene (CDNB, 8.5-fold variation), cumene hydroperoxide (CHP, 5-fold variation), and p-nitrophenyl acetate (NPA, 4-fold variation). No correlation was found among GST-AFBO activities and the presence of GST mu as determined by enzyme-linked immunosorbent assay (ELISA) or GST-trans-stilbene oxide (TSO) catalytic activity. Our observations support those of previous studies indicating that human liver cytosolic GSTs are relatively ineffective at conjugating AFBO. Furthermore, our data indicate that humans exhibit large inter-individual differences with respect to hepatic cytosolic GST conjugation of AFBO and certain other GST substrates.
Slone
D H
DH
Department of Environmental Health, University of Washington, Seattle 98195, USA.
Gallagher
E P
EP
Ramsdell
H S
HS
Rettie
A E
AE
Stapleton
P L
PL
Berlad
L G
LG
Eaton
D L
DL
D000293:Adolescent; D000328:Adult; D016604:Aflatoxin B1 / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D006224:Cricetinae; D003600:Cytosol / Q000201:enzymology; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D051381:Rats; D013045:Species Specificity; D013379:Substrate Specificity
C006426:aflatoxin B1-2,3-oxide; D016604:Aflatoxin B1; D005982:Glutathione Transferase