Structure-activity relationships in toxicity and carcinogenicity of aflatoxins and analogs.

Abstract

Summary Aflatoxins B1 and G1, in single doses, were lethal and had similar relative potencies in the duckling (50% lethal dose, 0.73 mg/kg versus 1.18 mg/kg) and in the rat (50% lethal dose, 1.16 mg/kg versus 2 to 4 mg/kg). Aflatoxins B2 and G2 were less potent in the duckling (50% lethal dose, 1.76 mg/kg versus 2.83 mg/kg) and were nontoxic to rats at doses of 200 mg/kg. Aflatoxin B1 induced hepatocellular carcinomas in rats dosed by stomach tube, the optimum carcinogenic regimen being 1.5 mg/rat given in 40 equal doses over 8 weeks. With this dosing regimen, aflatoxin G1 was carcinogenic to rat liver at doses of 2.0 and 1.4 mg/animal and also induced adenocarcinomas of the kidneys in 4/26 rats. When given by i.p. injection, aflatoxin B2 at a total dose of 150 mg/rat (40 equal doses over 8 weeks) induced hepatocellular carcinomas in 4/9 rats. Aflatoxin B1 dosed according to a comparable regimen induced liver tumors in 9/9 animals at a total dose of 1.3 mg per rat. Multiple s.c. injection of aflatoxin B1 resulted in sarcomas at the injection site in 9/9 rats within 44 to 58 weeks after a total dose of 0.4 mg/rat over 20 weeks. Aflatoxin B2 at a total dose of 12 mg/rat according to the same treatment schedule induced no tumors in 10 rats killed after 78 to 86 weeks. Tetrahydrodeoxyaflatoxin B1 and 3 synthetic compounds containing the substituted coumarin portion of the aflatoxin B configuration were nontoxic and noncarcinogenic at doses 100 to 200 times higher than aflatoxin B1. Collectively, these results indicate that the furofuran moiety of the aflatoxin structure is essential for toxic and carcinogenic activity. Moreover, the presence of the double bond in the terminal furan ring is an important determinant of potency, particularly for acute and chronic effects in rats. The importance of the substituents on the lactone portion of the molecule is also illustrated by the difference in potency of aflatoxins B1 and G1 in all systems studied.