In vitro effects of aflatoxin B1 on the uptake of 14C-orotic acid into kidney, liver and muscle tissue of the Mongolian gerbil, Meriones unguiculatus.

Abstract

Aflatoxins are a mixture of highly toxic metabolites produced by certain strains of the mold Aspergillu8 ~avu~ a contaminant of groundnuts and other grains. The chemical structures for these potent hepatotoxic and hepatocarcinogenic agents have been studied extensively and aflatoxin B I (AFB I) has been found to be the most abundant and toxic metabol~te (B~TLER 1966). A major area of study involving the aflatoxins has dealt with their mechanism of action. Often severe inhibition of protein synthesis by the cell can be measured by uptake and incorporation of various labeled precursors of protein and nucleic acids (SMITH 1963, CLIFFORD & REES 1966, 1967). One investigator reported inhibition Of nuclear and nucl~olar RNA synthesis (30% and 85%, respectively) as measured by 14C-orotic acid incorporation in Other work with rats showed rat livers (LEFARGE et al. 1966). i~ no inhibition of incorporation of C-orotic acid in in vivo studies of the nucleotide pool, but immediate inhibition in in vitro studies. However, the authors did find inhibition of nucleotide precursors into nuclear RNA and postulated inhibition of RNA polymerase as a possible explanation (CLIFFORD & REES 1967). Later work subsequently explored this hypothesis corroborating it for RNA polymerase and implicating metabolites of AFB I as the active intermediate forms responsible for the inhibitmon (AKINRIMIST et al. 1974). A metabolite of AFB I was also suggested as the actual inhibitor of RNA synthesis in another work where the incorporation of RNA precursors, 14C-orotic acid and 3H-orotic acid, was markedly inhibited by low levels of AFH I and AFGI, but not AFB 2 and AFG 2 (MCINTOSH et al. 1976). Most of the literature involving measurement of uptake and incorporation of precursors has dealt m~inly with the effects on rats and few recent studies have used 14C-orotic acid. It was the purpose of this study to determine the effects of AFB_ on the uptake of 14C-orotic acid into kidney, liver and muscle tissue of the Mongolian gerbil, Meriones unguicula~s. This animal appears to be less sensitive to the toxin than the rat (GODY & NEAL 1976, LLEWELLYN & THOMEN 1978).