Effects of dietary oltipraz and ethoxyquin on aflatoxin B1 biotransformation in non-human primates.
Following aflatoxin B1 (AFB) exposure, rats readily develop liver tumors. However, treatment of rats with a variety of compounds, including the synthetic dithiolthione oltipraz and the antioxidant ethoxyquin, protects these rodents from AFB-induced hepatocarcinogenesis. Several epidemiological studies strongly suggest that AFB is also a causative agent of liver cancer in humans. However, relatively little is known about the efficacy of cancer chemoprevention in human and non-human primates. To this end, we examined the effects of chemopreventive agents on AFB metabolism in non-human primates. Hepatic aflatoxin B1 metabolism profiles of macaque (Macaca nemestrina) and marmoset (Callithrix jacchus) monkeys were determined and compared to humans. Quantitatively, the oxidative metabolism of this mycotoxin was similar in the three primate species. In contrast to macaques, both humans and marmosets lacked AFB-glutathione conjugating activity. It was concluded that marmosets resembled human AFB metabolism more closely than the macaques, and therefore, marmoset monkeys were chosen for this study. Eleven adult male marmosets were randomly assigned to three groups. Animals received the synthetic dithiolthione oltipraz, the antioxidant ethoxyquin, or vehicle only. In addition, two single doses of AFB were also administered orally before and after animals were treated with aforementioned compounds. Both oltipraz and ethoxyquin induced aflatoxin B1-glutathione conjugating activity in the livers of some but not all marmosets. In addition, 10 microM oltipraz inhibited cytochrome P450-mediated activation of AFB to the ultimate carcinogenic metabolite, aflatoxin B1-8,9-epoxide, in vitro, up to 51%. Furthermore, animals treated in vivo with oltipraz, but not ethoxyquin, exhibited a significant reduction (53% average) in AFB-DNA adduct formation relative to the control animals (p < 0.05). Together, our data suggest that chemoprevention is also effective in primates; however, most likely to a lesser degree than in rodents.
Bammler
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TK
Department of Environmental Health, University of Washington, Seattle 98195, USA.
Slone
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Eaton
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D016604:Aflatoxin B1 / Q000493:pharmacokinetics*; D000418:Albumins / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001711:Biotransformation; D002144:Callithrix; D002273:Carcinogens / Q000493:pharmacokinetics*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004032:Diet; D005015:Ethoxyquin / Q000008:administration & dosage / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008254:Macaca nemestrina; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D013045:Species Specificity; D013723:Teratogens / Q000493:pharmacokinetics*; D013871:Thiones; D013876:Thiophenes
D000418:Albumins; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D018736:DNA Adducts; D011719:Pyrazines; D013723:Teratogens; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D016604:Aflatoxin B1; D005015:Ethoxyquin; D005982:Glutathione Transferase