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Aflatoxin B₁-2,3-oxide as a Probable Intermediate in the Covalent Binding of Aflatoxins B₁ and B₂ to Rat Liver DNA and Ribosomal RNA in Vivo¹

McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706

Administration of [³H]aflatoxin B₂ (2,3-dihydroaflatoxin B₁) (AFB₂) to male rats resulted in levels of hepatic DNA- and ribosomal (r)RNA-aflatoxin adducts that were about 1% of those for rats given [³H]aflatoxin B₁ (AFB₁). The levels of hepatic protein-aflatoxin adducts were 35 to 70% as great for AFB₂-treated as compared to AFB₁-treated rats.

Mild acid hydrolysis of hepatic DNA and rRNA from rats given [³H]AFB₁ or [³H]AFB₂ yielded 2,3-dihydro-2,3-dihydroxyaflatoxin B₁ and two other major tritiated products that were separable by high-pressure liquid chromatography. With 2-hr hydrolyses approximately 77 and 54% of the ³H from the hepatic DNA of rats given [³H]AFB₁ or [³H]AFB₂, respectively, and 40 and 32%, respectively, of the ³H from the rRNA of rats given [³H]AFB₁ or [³H]AFB₂ were isolated as these products. One of the tritiated products was converted to 2,3-dihydro-2,3-dihydroxy-aflatoxin B₁ on further mild acid hydrolysis. The high levels of the dihydrodiol and its precursor in the hydrolysates, especially when the 35% loss of added 2,3-dihydro-2,3-dihydroxyaflatoxin B₁ under the hydrolysis conditions is taken into account, indicate that aflatoxin B₁-2,3-oxide is a major ultimate precursor of the nucleic acid-bound derivatives formed from both AFB₁ and AFB₂ in rat liver. From these data, AFB₂ appears to be converted to AFB₁ in the rat liver in vivo to an extent (about 1%) that is comparable to the ratio of hepatocarcinogenicities of these compounds in this species.

The levels of hepatic DNA-bound adducts from [³H]AFB₁ were about one-half of the control level in hypophysectomized rats, while the levels of the rRNA- and protein-aflatoxin adducts were similar to those of the controls. The levels of the hepatic macromolecule-bound adducts were 10 to 30% of the control levels in phenobarbital-treated rats. The levels of macromolecule-bound adducts of AFB₁ in kidney, spleen, and small intestine were much lower than those of liver. The inhibitory action of phenobarbital on AFB₁-induced hepatocarcinogenesis was confirmed; administration of benz(a)anthracene or high levels of ascorbic acid with AFB₁ did not alter the tumor incidence.

¹ This work was supported by Grant CA-07175, CA-15785, and CRTY-5002 of the National Cancer Institute, USPHS.

² Present address: Chester Beatty Research Institute, Pollards Wood Research Station, Nightingales Lane, Chalfont St. Giles, Buckinghamshire HP8 4SP, England.

³ Visiting Professor of Oncology, University of Wisconsin, 1975 to 1976 and recipient of USPHS International Research Fellowship 1-F05-TWO-2267. Present address: Department of Biochemistry, College of Medicine, National Taiwan University, Taipel, Taiwan, Republic of China.

⁴ To whom requests for reprints should be addressed.

Received 8/ 9/76. Accepted 10/13/76.

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