Fibrates induce hepatic peroxisome and mitochondrial proliferation without overt evidence of cellular proliferation and oxidative stress in cynomolgus monkeys.
There is little primate risk factor data in the literature evaluating the relationship between proposed mechanisms of PPAR agonist-induced hepatocarcinogenesis at clinically relevant therapeutic exposures. These studies were conducted to characterize the hepatic effects of fenofibrate and ciprofibrate in the cynomolgus monkey. Male cynomolgus monkeys were given fenofibrate (250, 1250 or 2500 mg/kg/day) or ciprofibrate (3, 30, 150 or 400 mg/kg/day) for up to 15 days. The highest doses used were approximately 4 times (fenofibrate) and 9.4 times (ciprofibrate) the human therapeutic exposure for these agents based on AUC (area under the curve). For both compounds, there was a treatment-related increase in liver weight and periportal hepatocellular hypertrophy, which was related to increases in peroxisomes (up to 2.8 times controls) and mitochondria (up to 2.5 times controls). An increase in smooth endoplasmic reticulum probably contributed to the hypertrophy. There was no indication of cell proliferation as determined by the number of mitotic figures and this was confirmed by evaluating cell proliferation by immunohistochemical staining for the Ki-67 antigen. Consistent with the findings by light microscopy, there was no treatment-related effect on the level of mRNA for proteins known to be involved in the control of hepatocyte cell division or apoptosis (e.g. P21, Cyclin D1, PCNA, CDKN1A). Furthermore, there was minimal indication of oxidative stress. Thus, there was no evidence of lipofuscin accumulation, and there was no remarkable increase in the mRNA levels for most proteins known to respond to oxidative stress (e.g. catalase, glutathione peroxidase). A mild induction in the mRNA levels of cellular beta-oxidation and detoxification enzymes (e.g. acyl CoA oxidase, thioredoxin reductase) was observed. Collectively, the data from these studies suggest that the primate responds to PPARalpha agonists in a manner that is different from the rodent suggesting that the primate may be refractory to PPAR-induced hepatocarcinogenesis.
Hoivik
Debie J
DJ
GlaxoSmithKline Pharmaceuticals, Five Moore Drive, Research Triangle Park, North Carolina, USA and Upper Merion, Pennsylvania, USA. debie.j.hoivik@gsk.com
Qualls
Charles W
CW
Mirabile
Rosanna C
RC
Cariello
Neal F
NF
Kimbrough
Carie L
CL
Colton
Heidi M
HM
Anderson
Steven P
SP
Santostefano
Michael J
MJ
Morgan
Ronda J Ott
RJ
Dahl
Ray R
RR
Brown
Alan R
AR
Zhao
Zhiyang
Z
Mudd
Paul N
PN
Oliver
William B
WB
Brown
H Roger
HR
Miller
Richard T
RT
D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D019540:Area Under Curve; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000633:toxicity*; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D018871:Endoplasmic Reticulum, Smooth / Q000187:drug effects / Q000378:metabolism; D011345:Fenofibrate / Q000633:toxicity*; D058607:Fibric Acids; D020869:Gene Expression Profiling; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008940:Mitotic Index; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D058607:Fibric Acids; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019938:Cyclin D1; D002995:Clofibric Acid; D002374:Catalase; D005979:Glutathione Peroxidase; D042962:Acyl-CoA Oxidase; D013880:Thioredoxin-Disulfide Reductase; C019304:ciprofibrate; D011345:Fenofibrate