Hepatic hyperplasia and cancer in rats: metabolic alterations associated with cell growth.
OBJECTIVE
We showed previously that the peroxisome proliferators di(2-ethylhexyl)phthalate (DEHP), clofibrate, and 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hydroxyl)acetamide (BR931) alter hepatic sex steroid metabolism and receptor expression during induction of hepatic hyperplasia and hepatocellular carcinoma (HCC) in rats. The aim of this study was to identify metabolic changes associated with cell growth during hyperplasia and HCC.


METHODS
Hepatic hyperplasia was induced in male rats by a diet containing DEHP and clofibrate for 3-60 days. HCC was induced by feeding a diet containing BR931, a more potent hepatocarcinogen, for 10 months.


RESULTS
Cholesterol biosynthesis was depressed in hyperplastic livers but increased in HCC. Glucose-6-phosphate dehydrogenase (G6PD) activity was inhibited in hyperplastic liver as well as in HCC, whereas malic enzyme activity increased severalfold. Protein and messenger RNA (mRNA) levels for both G6PD and malic enzyme increased in hyperplastic livers and HCC. mRNA levels for 3-hydroxy-3-methylglutaryl-coenzyme A reductase decreased in hyperplasia and increased in HCC, whereas low-density lipoprotein receptor mRNA increased in hyperplasia and decreased in HCC.


CONCLUSIONS
Neoplastic cells acquire a growth advantage by their capacity to synthesize cholesterol and obtain reduced nicotinamide adenine dinucleotide phosphate by the malic enzyme pathway when G6PD activity is inhibited by peroxisome proliferators.
Rao
K N
KN
Department of Pathology, University of Pittsburgh Medical Center, Pennsylvania 15213-2582, USA. rao@med.pitt.edu
Elm
M S
MS
Kelly
R H
RH
Chandar
N
N
Brady
E P
EP
Rao
B
B
Shinozuka
H
H
Eagon
P K
PK
D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens; D002455:Cell Division; D002784:Cholesterol / Q000096:biosynthesis; D002994:Clofibrate; D004051:Diethylhexyl Phthalate; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006965:Hyperplasia; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008291:Malate Dehydrogenase / Q000378:metabolism; D008297:Male; D009249:NADP / Q000096:biosynthesis; D010427:Pentose Phosphate Pathway; D011743:Pyrimidines; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011973:Receptors, LDL / Q000378:metabolism
D002273:Carcinogens; D011743:Pyrimidines; D012333:RNA, Messenger; D011973:Receptors, LDL; D009249:NADP; C016908:pirinixil; D002784:Cholesterol; D004051:Diethylhexyl Phthalate; D006903:Hydroxymethylglutaryl CoA Reductases; D008291:Malate Dehydrogenase; D005954:Glucosephosphate Dehydrogenase; D002994:Clofibrate