HEPATIC HYPERPLASIA AND CANCER IN RATS - METABOLIC ALTERATIONS ASSOCIATED WITH CELL-GROWTH

Background & Aims: We showed previously that the peroxisome proliferat ors di(2-ethylhexyl)phthalate (DEHP), clofibrate, and 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hyduoxyl)acetamide (BR931) alter h epatic sex steroid metabolism and receptor expression during induction of hepatic hyperplasia and hepatocellular carcinoma (HCC) in rats. Th e aim of this study was to identify metabolic changes associated with cell growth during hyperplasia and HCC. Methods: Hepatic hyperplasia w as induced in male vats by a diet containing DEHP and clofibrate for 3 -60 days. HCC was induced by feeding a diet containing BR931, a move p otent hepatocarcinogen, for 10 months. Results: Cholesterol biosynthes is was depressed in hyperplastic livers but increased in HCC. Glucose- 6-phosphate dehydrogenase (G6PD) activity was inhibited in hyperplasti c liver as well as in HCC, whereas malic enzyme activity increased sev eralfold. Protein and messenger RNA (mRNA) levels for both G6PD and ma lic enzyme increased in hyperplastic livers and HCC. mRNA levels for 3 -hydroxy-3-methylglutaryl-coenzyme A reductase decreased in hyperplasi a and increased in HCC, whereas tow-density lipoprotein receptor mRNA increased in hyperplasia and decreased in HCC. Conclusions: Neoplastic cells acquire a growth advantage by their capacity to synthesize chol esterol and obtain reduced nicotinamide adenine dinucleotide phosphate by the malic enzyme pathway when G6PD activity is inhibited by peroxi some proliferators.