Dexamethasone selectively inhibits WY14,643-induced cell proliferation and not peroxisome proliferation in mice.
It has been proposed that the hepatocellular proliferation induced by peroxisome proliferators may occur through an indirect mechanism involving cytokine release as opposed to direct regulation of cell growth genes by PPARalpha. We compared the induction of peroxisome proliferation and cell proliferation in C57Bl/6 mice treated with 100 mg/kg/day WY14,643 in the presence or absence of increasing doses of dexamethasone (DEX), an inhibitor of the release of proinflammatory cytokines. Biochemical markers of peroxisome proliferation, including fatty acyl-CoA oxidase activity, CYP4A content, and liver-to-body-weight ratios were markedly increased in the WY14,643-treated mice. DEX coadministration, up to a maximum dose of 50 mg/kg/day, did not prevent the induction of these parameters. Acyl-CoA oxidase mRNA levels increased 5-fold with WY14,643 treatment and 15-fold with DEX coadministration at 5 mg/kg/day. ApoCIII mRNA levels were decreased by 50% in WY14,643-treated mice. DEX alone at 5 mg/kg/day increased the ApoCIII mRNA 4-fold, but WY14,643 coadministration also inhibited this induction by greater than 50%. In addition, immunohistochemical detection of peroxisomes with anti-PMP-70 antibody demonstrated marked increase in hepatocellular peroxisomes in WY14,643-treated mice regardless of DEX treatment. In contrast, coadministration of DEX at 2 mg/kg/day partially inhibited the hepatocyte proliferation response (measured by BrdU incorporation or Ki-67 immunohistochemical detection). Moreover, DEX at doses of 5 mg/kg/day or higher completely inhibited the induction of cell proliferation and, at these higher doses, reduced the cell proliferation rate to levels below the vehicle-treated control mice. Our studies clearly demonstrate that the hepatocellular proliferation induced by a peroxisome proliferator can be modulated independently of the other pleiotropic effects usually induced by these agents, suggesting an indirect mechanism of hyperplasia.
Lawrence
J W
JW
Department of Safety Assessment, Merck and Co., Inc., Sumneytown Pike, WP45A-210, West Point, PA 19486, USA. jeff_lawrence@merck.com
Wollenberg
G K
GK
Frank
J D
JD
DeLuca
J G
JG
D042962:Acyl-CoA Oxidase; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000096:biosynthesis / Q000235:genetics; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D020025:Peroxisome Proliferators / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011743:Pyrimidines / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology
D000893:Anti-Inflammatory Agents; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003907:Dexamethasone; C006253:pirinixic acid; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase