Hepatic Metabolism of Perfluorinated Carboxylic Acids: A Nuclear MagneticResonance Investigation In vivo

摘要

This report outlines our progress regarding toxicological studies of perfluoro- n-octanoic acid (PFOA) and perfluoro-n-decanoic acid (PFDA). These Air Force chemicals belong to a class of compounds known as peroxisome proliferators (PP). Many PP cause hepatotoxicity and carcinogenesis in rodents. The mechanisms are unknown and represent an active area of research. Recent studies have demonstrated specific effects of PFDA treatment on hepatic phospholipid and carbohydrate metabolism. PFDA alters hepatic glucose transport. PFDA-treated rats showed rates of glucose transport which were 2-fold less than controls. PFDA treatment also caused a 3-fold increase in liver diacylglycerol (DAG): PFOA had no effect. This DAG is derived from phosphatidylcholine via phospholipase C activity. Since DAG stimulates protein kinase C (PKC), these data suggest that the hepatotoxic effects of PFDA may be initiated through a PKC response. Accordingly, experiments are in progress to investigate the effects of PFDA on liver PKC activity; preliminary data are presented herein. In other studies, preliminary data indicate that the influence of PFDA on phospholipid metabolism occurs at doses well below the LD50. Also, in studies involving C8-C11 perifluoro- carboxylic acids, only chain lengths > C9 affect phospholipid metabolism. These data suggest that the metabolic effects may be related to the compound's ability to diffuse into membranes. This research furthers our understanding of the mechanisms involved in the hepatotoxicity associated with these Air Force chemicals.