Fibrates induce hepatic peroxisome and mitochondrial proliferation without overt evidence of cellular proliferation and oxidative stress in cynomolgus monkeys

Abstract

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.

Fenofibrate Metabolism in the Cynomolgus Monkey using Ultraperformance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry-Based Metabolomics

“…Taurine conjugates were of higher abundance than other metabolites as detected by UPLC-QTOFMS. By quantitation of the primary metabolite FA and newly identified taurine metabolites, exposure to FA at the high dose was approximately 7 times that at the low dose (Table 3), which was similar to the 4 times reported previously (2500 mg/kg/day versus 200 mg/kg/day) (Hoivik et al, 2004). In addition, exposure to RFAT was more than one-fourth that of FA by molar concentration, indicating a potential warning sign of metabolite safety; however, the phenotype analysis showed that fenofibrate was well tolerated in cynomolgus monkeys (Supplemental Fig.…”

“…However, fenofibrate was reported to be a peroxisome proliferator and to produce hepatocarcinogenesis in some rodent species, but there is no evidence for hepatotoxic or carcinogenic effects of these compounds in humans or NHPs (Hoivik et al, 2004;Peters et al, 2005). In mice, PPAR␣ was found to mediate the liver toxicity and cancer properties of fibrate drugs and related PPAR␣ agonists (Ward et al, 1998;Peters et al, 2000).…”

“…In addition, chronic administration of fibrates to rodents causes hepatocellular carcinoma. It is interesting to note that both humans and nonhuman primates are refractory to hepatocellular carcinoma caused by PPAR␣ agonists (Reddy et al, 1980;Rao and Reddy, 1987;Ward et al, 1998;Klaunig et al, 2003;Hoivik et al, 2004), yet the mechanism behind the species-related difference of susceptibility to these drugs remains to be firmly established (Peters et al, 2000;Hoivik et al, 2004). Some metabolites of PPAR␣ agonists have been reported to cause toxicity and complex drug-drug interactions, underscoring the need for detailed metabolic studies of PPAR␣ agonists (Sallustio et al, 1997;Backman et al, 2002;Prueksaritanont et al, 2002;Shitara et al, 2004).…”

Flavivirus Infection Impairs Peroxisome Biogenesis and Early Antiviral Signaling

“…A physical or functional relationship between flavivirus and mitochondria has not been demonstrated, but it is well documented that peroxisomes and mitochondria are in close communication and share proteins, including the antiviral signaling protein MAVS (25). Moreover, pharmacological agents, such as fibrates, which are known to dramatically increase peroxisome proliferation, similarly affect mitochondria (26).…”

Sensitivity of liver metabolism in jerboa (Jaculus orientalis) to ciprofibrate, a peroxisome proliferator

“…The treatment of primates with ciprofibrate leads to an increase in hepatic mitochondria and peroxisomes, without clear evidence of cellular proliferation (3). Notably, El Kebbaj et al (4) revealed that the jerboa (Jaculus orientalis) has unique peroxisome properties in contrast to rats, responding in a moderate manner to peroxisome proliferators such as ciprofibrate and experiencing neither hepatomegaly nor the promotion of liver cell DNA replication.…”