Date of Award
Doctor of Philosophy
Dileep S. Sachan
Ann Draughon, Walter R. Farkas, Naima Moustaid, Mary Sue Younger
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.
Yatim, Ayub Mohd, "Mechanisms of Carnitine-Mediated Modulation of Aflatoxin B1-DNA Adduct Formation. " PhD diss., University of Tennessee, 1996.