Regulation of fatty acid biosynthesis as a possible mechanism for the mitoinhibitory effect of fumonisin B-1 in primary rat hepatocytes

The mitoinhibitory effect of fumonisin B-1 (FB1) on the mitogenic response of epidermal growth factor (EGF) was investigated in primary hepatocyte cul tures with respect to the alterations in the omega 6 fatty acid metabolic p athway. Fatty acid analyses of hepatocytes showed that EGF treatment result ed in a significant decrease in the relative levels of 20:4 omega 6 (arachi donic acid) and an increase in 18:2 omega 6 (linoleic acid). Supplementatio n of the hepatocyte cultures with 20:4 omega 6 in the absence of EGF result ed in an increase in the total omega 6 and omega 6/omega 3 fatty acid ratio . Addition of 20.5 omega 3 (eicosapentaenoic acid) resulted in an increase of the relative levels of the long chain omega 3 fatty acids at the expense of the omega 6 fatty acids. When 26:4 omega 6 and 20:5 omega 3 was added i n the presence of EGF, the mitogenic response of EGF was increased and decr eased respectively. When compared to the fatty acid profiles in the absence of EGF, the decreased mitogenic response coincided with a decrease of tota l omega 6 fatty acids and total polyunsaturated fatty acids (PUFA). In addi tion, the saturated and mono-unsaturated fatty acids increased and the poly unsaturated/saturated (P/S) fatty acid ratio decreased which implied a more rigid membrane structure. Addition of prostaglandin E-2, (PGE(2)) and pros taglandin E-1 (PGE(1)) stimulated and inhibited the mitogenic response resp ectively. Ibuprofen, a known cyclooxygenase inhibitor, and FB1 inhibited th e EGF-induced mitogenic response in a dose-dependent manner. The mitoinhibi tory effect of FB1 on the EGF response was counteracted by the addition of PGE(2). FB1 also disrupts the omega 6 fatty acid metabolic pathway in prima ry hepatocytes, resulting in the accumulation of C18:2 omega 6 in phospatid ylcholine and triacylglicerol. The disruption of the omega 6 fatty acid met abolic pathway and/or prostaglandin synthesis is likely to be an important event in the mitoinhibitory effect of FB1 on growth factor responses. (C) 1 999 Harcourt Publisher Ltd.