Inhibition of aflatoxin Ml excretion in rat urine during dietary intervention with oltipraz.
4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) is an effective chemopreventive agent against several classes of carcinogens in many target organs. Induction of carcinogen detoxication enzymes, particularly glutathione S-transferases, appears to be an important component of the protective actions of oltipraz. It has recently been observed that addition of oltipraz to rat liver microsomes or to cultured human hepatocytes blocks the oxidative metabolism of aflatoxin B1 (AFB1) to its 8,9-oxide and the hydroxylated derivative aflatoxin Ml (AFM1). 0ltipraz is a competitive and perhaps irreversible inhibitor of cytochromes P450 1A2 and 3A4. To determine whether oltipraz can affect cytochrome P450-dependent metabolism of AFB1 in vivo we have assessed the effect of oltipraz on the urinary excretion of oxidative metabolites of AFB1 before, during and after a transient intervention. Male F344 rats, housed individually in glass metabolism cages, were gavaged daily with 25 microg [3H]AFB1 for 28 consecutive days. Starting on day 6 and extending to day 16 half of the rats were fed a diet supplemented with 0.075% oltipraz. Sequential 24 h urine samples were collected and a subset analyzed for AFB1 metabolites. AFM1 was the major metabolite detected in all urine samples, accounting for 2-6% of the administered dose. The excretion of AFM1 was greatly reduced (77%) during the active phase of the intervention, when oltipraz was added to the diet, but rapidly returned to control levels after cessation of oltipraz administration. This inhibition of AFM1 excretion was not seen in animals receiving oltipraz by gavage 24 h prior to dosing with AFB1. Collectively these data are consistent with the view that oltipraz or a short-lived metabolite inhibits cytochrome P450 1A2 in vivo.
Scholl
P
P
Department of Environmental Sciences, The Johns Hopkins University, School of Hygiene and Public Health, Baltimore, MD 21205, USA.
Musser
S M
SM
Kensler
T W
TW
Groopman
J D
JD
D016604:Aflatoxin B1 / Q000378:metabolism / Q000493:pharmacokinetics; D016607:Aflatoxin M1 / Q000652:urine*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004032:Diet; D004305:Dose-Response Relationship, Drug; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000178:diet therapy* / Q000652:urine; D008297:Male; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D016607:Aflatoxin M1; C026209:oltipraz; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1