Carcinogenesis, Vol 18, 107-114, Copyright © 1997 by Oxford University Press
FK Kessler and JK Ritter
We report here that rats possess a hitherto unrecognized xenobiotic-
inducible hepatic 7,8-dihydro-7,8-diol-benzo[a]pyrene (BPD) UDP-
glucuronosyltransferase (UGT) activity. BPD UGT activity is induced in
female F344 rat liver by treatment with the selective Phase 2 conjugation
enzyme inducer oltipraz [4-methyl-5-(2-pyrazinyl)-1,2- dithiole-3-thione at
75-450 mg/kg per day for 3 days] and also by a polycyclic aromatic
hydrocarbon-type inducer, beta-naphthoflavone (80 mg/kg per day for 3
days). Incubations of oltipraz-treated rat liver microsomes with racemic
trans BPD (100 microM) resulted in formation of two fluorescent
glucuronides that were resolved by silica thin layer chromatography (Rf 0.5
and 0.6). Incubations with either the (-) or (+) trans BPD isomers resulted
in selective formation of the Rf 0.5 [designated -DS, for (-) diol
specific] or Rf 0.6 [designated +DS, for (+) diol specific] glucuronide,
respectively. The -DS and +DS BPD glucuronides were fluorescent under long
wave ultraviolet irradiation, dependent on the presence of UDP-glucuronic
acid in the incubation, and were beta-glucuronidase-sensitive. The inducing
effect of oltipraz on BPD UGT activity was dose-dependent. The mean BPD UGT
activity of the vehicle-treated control group was 0.05 +/- 0.02 nmol/mg per
min compared with 0.53 +/- 0.07 nmol/mg per min in the group treated with
oltipraz (450 mg/kg per day for 3 days) (P < 0.001). The apparent Km of
the induced BPD UGT for BPD was 20 microM, suggesting that the enzyme has
the capacity to bind and turnover BPD under physiological conditions.
Pretreatment with beta-naphthoflavone, but not phenobarbital, induced BPD
UGT activity to approximately the same extent as oltipraz. Neither oltipraz
nor beta-naphthoflavone exhibited induction of BPD UGT in livers of
homozygous Gunn rats, which lack functional UGT1-encoded isozymes. We
conclude that the oltipraz- and polycyclic hydrocarbonresponsive BPD UGT is
a member of the UGT1 family. The role of this isoform as a modifier of
susceptibility to carcinogenesis elicited by B[a]P remains to be
determined.
ARTICLES
Induction of a rat liver benzo[a]pyrene-trans-7,8-dihydrodiol glucuronidating activity by oltipraz and beta-naphthoflavone
Department of Pharmacology and Toxicology, School of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
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