GLUTATHIONE S-TRANSFERASE-PLACENTAL FORM EXPRESSION AND PROLIFERATIONOF HEPATOCYTES IN FUMONISIN B-1-TREATED MALE AND FEMALE SPRAGUE-DAWLEY RATS

Fumonisin B-1 (FB1), a mycotoxin produced by a common corn contaminant Fusarium moniliforme and a hepatocarcinogen in rats, has been previou sly suggested to act as a poor initiator, but a better promoter of gam ma-glutamyltranspeptidase (GGT)-positive rat liver preneoplastic lesio ns. Using glutathione S-transferase-placental form (GSTP) as a more se nsitive marker of initiation, we have further evaluated the initiating capacity of various doses of purified FB 1 administered (a) intraperi toneally (IP) to male Sprague-Dawley (SD) rats for 4 days and (b) oral ly (PO) to male and female SD rats for 11 days. Compared to their resp ective controls, significant increases in GSTP-positive hepatocytes we re observed in male rats administered FB1 IP at 10 mg/kg body weight/d ay for 4 days, as well as in male and female rats treated with 35 and 75 mg/kg body weight/day FB1 PO for 11 days. The percentage section ar ea of liver occupied by GSTP-positive mini-foci comprising of three to 12 cells was increased significantly in male rats given 10 mg/kg FB1 IP, or in PO-treated males and females with 75 mg/kg FB1. Both TP and PO FB1 treatments resulted in dose-related enhanced hepatocyte prolife ration as measured by proliferating cell nuclear antigen (PCNA) labeli ng with significant increases in the number of PCNA-positive nuclei at the same IP and PO dose levels where the number of GSTP-positive cell s were elevated. In all studies, enhanced PCNA and GSTP expression occ urred at FB1 doses which, based on serum biochemical and histopatholog ical data previously reported from our laboratory, were shown to be he patotoxic, Therefore, our data suggest that in a manner similar to kno wn genotoxic carcinogens, FB1 has the capacity to initiate GSTP-positi ve hepatocytes with their subsequent development into GSTP mini-foci a t exposure levels that induce enhanced hepatocyte proliferation in res ponse to liver toxicity. In SD rats, this occurs as early as within 4 days of IP treatment or 11 days of PO treatment. (C) 1998 Elsevier Sci ence Ireland Ltd.