INDUCTION OF CYTOCHROME P4504A BY THE PEROXISOME PROLIFERATOR PERFLUORO-N-OCTANOIC ACID

The influence of a single dose of the peroxisome proliferator, perfluoro-n-octanoic acid (PFOA) on hepatic and renal mixed-function oxidase activities has been examined in rats. Peroxisome proliferation was confirmed by increases in peroxisomal palmitoyl-CoA oxidation and carnitine acetyl transferase activity, particularly in liver. The liver was also more susceptible than the kidney to PFOA-dependent induction of the 12-hydroxylation of lauric acid, suggesting induction of the CYP4A sub-family. This was further confirmed by Western blot analyses, wherein an anti-CYP4A1 antibody revealed a substantial PFOA-dependent induction of CYP4A1 in a pattern similar to that observed for the classical peroxisome proliferator, clofibrate. In addition, using a cDNA probe to CYP4A1 in Northern blot analysis, PFOA treatment resulted in a marked increase in the steady state level of CYP4A1 mRNA, again more extensively in liver than in kidney. Taken collectively, our data provide compelling evidence that PFOA, like other peroxisome proliferators, is also an inducer of the CYP4A sub-family.