Carcinogenesis, Vol 18, 1343-1349, Copyright © 1997 by Oxford University Press
S Langouet, K Maheo, F Berthou, F Morel, D Lagadic-Gossman, D Glaise, B Coles, B Ketterer and A Guillouzo
The success of oltipraz (OPZ) [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-
thione] as a chemoprotective agent against aflatoxin B1 (AFB1)-induced
hepatocarcinogenesis in the rat is thought to depend principally on its
ability to enhance detoxication by inducing phase II enzymes, especially
glutathione transferases. However, in primary cultures of human
hepatocytes, we recently demonstrated that OPZ also has an important
inhibitory effect on the major cytochromes P450 (CYPs) of human hepatic
AFB1 metabolism. This has prompted a detailed study of the effect of OPZ on
some CYPs involved in metabolism of AFB1 in the rat. Primary cultures of
rat hepatocytes behaved similarly to human hepatocytes and responded to OPZ
by inhibition of ethoxyresorufin-O- deethylase (EROD) and
pentoxyresorufin-O-depentylase (PROD) activities mainly associated,
respectively, with CYP1A and CYP2B. A time-course shows that this
inhibition is largely reversible, with EROD and PROD activities reaching a
minimum at 12 h and tending towards control values within 24 h. As is to be
expected, the incubation of isolated microsomes with OPZ also inhibits
CYP1A and 2B. The effect of OPZ on CYP1A is not a phenomenon limited to
cells in culture, but also occurs in vivo. Using the whole animal, we were
able to demonstrate that OPZ also transiently inhibited CYP1A activity in a
rat given caffeine, by measuring the amounts of methylxanthines found in
the serum. However, microsomes isolated from rats, that had been treated
with OPZ in vivo, show no such inhibition, presumably because, since OPZ is
a reversible inhibitor, it dissociates and is lost during the course of
conventional procedures of microsomal preparation. This explains some
earlier failures in studies of isolated microsomes to observe the
inhibition of CYPs by OPZ. In addition to inhibiting their enzymatic
activity, OPZ is also an inducer of CYP1A and 2B as shown by the increased
levels of their mRNAs and of caffeine metabolism in vivo after 24 h or
more. It is concluded that the mechanism of chemoprotection by OPZ, of
toxic chemical metabolism in the rat, is complex and involves competitive
inhibition of activation succeeded by induction of the enzymes of both
activation and detoxication.
ARTICLES
Effects of administration of the chemoprotective agent oltipraz on CYP1A and CYP2B in rat liver and rat hepatocytes in culture
Unite Detoxication et Reparation Tissulaire, Faculte de Pharmacie, Universite de Rennes I and INSERM U49, CHRU Pontchaillou, Rennes, France.
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