Mechanisms of Carnitine-Mediated Modulation of Aflatoxin B₁-DNA Adduct Formation

The main purpose of this study was to investigate the possible mechanism(s) of L-carnitine-mediated modulation of AFB₁-DNA adducts formation. The first part of the study investigated the effect of increased doses of carnitine on AFB₁ binding to macromolecules, AFB₁ uptake, activity of glutathione S-transferase (GST), and total glutathione concentrations in freshly isolated hepatocytes. Carnitine dose was significantly correlated with the formation of AFB₁-DNA adduct ( r = -0.68;p = 0.0002 ), AFB₁-protein adduct (r = 0.58;p = 0.017), but not AFB₁-RNA adduct (r = 0.14;p = 0.604). There was no effect of carnitine on the uptake of AFB₁ by the hepatocytes or on the activity of GST. Carnitine protected AFB₁-induced reduction of total glutathione concentration in the hepatocytes, which may contribute to the overall protective effect of carnitine. The second part of the study investigated the effect of carnitine on the binding of microsomal-activated AFB₁ to exogenous DNA and protein. Carnitine significantly decreased the binding of activated AFB₁ to DNA. It is postulated that carnitine reduced this binding by inhibiting the AFB₁-epoxide formation and/or binding of AFB₁-epoxide to DNA. This effect of carnitine was not very specific because acetylcarnitine and γ-aminobutyric acid were equally effective in reducing AFB₁-DNA adduct formation; however, choline and glycine had no effect. Carnitine enhanced the binding of AFB₁ as well as microsomal-activated AFB₁ to rat plasma proteins and bovine serum albumin. This mode of carnitine actions is proposed to be another mechanism of carnitine-mediated reduction of AFB₁-DNA adduct formation.