17␤-Estradiol (E2) induces cathepsinThe aryl hydrocarbon (Ah) receptor protein is expressed in laboratory animals and humans and in mammalian cells in culture (54,65). Although the endogenous ligand(s) for this receptor has not been identified, several different classes of compounds reversibly bind the Ah receptor, and these include the polynuclear and polyhalogenated aromatic hydrocarbons (42,54,57,59,65,67). 3-Methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are prototypical aromatic hydrocarbons which exhibit high-affinity binding (K d Յ 1 nM) for the Ah receptor (44, 58) and have been utilized for characterizing Ah receptor-mediated responses.TCDD induces a broad spectrum of biochemical and toxic responses including a wasting syndrome, immune suppression, hepatotoxicity, developmental and reproductive toxicity, carcinogenicity, dermal toxicity, alteration of endocrine response pathways, and modulation of diverse enzyme activities (26,29,59,73,82). The induction of CYP1A1 gene expression by TCDD and 3-methylcholanthrene has been extensively investigated, and the results indicate that the Ah receptor acts as a nuclear ligand-induced transcription factor (13,29,73,82).After treatment of animals or cells with TCDD, there is a rapid formation of a heterodimeric nuclear Ah receptor complex (19) which consists of the ligand-binding protein (7) and the Ah receptor nuclear translocator (Arnt) protein (31). The unbound Ah receptor is associated with heat shock protein 90 (48,55,60,61), and the subcellular distribution of these proteins in the absence of ligand is currently being investigated (60, 61). The nuclear Ah receptor complex interacts with cognate genomic sequences (dioxin or xenobiotic responsive elements [DREs and XREs, respectively]) in the 5Ј-promoter region of the CYP1A1 gene and transactivates CYP1A1 gene expression (15-17, 27, 34, 70, 83). There is evidence that this transactivation process is comparable for induction of CYP1A1 gene expression and induction of the expression of other members of the Ah gene battery, namely CYP1A2, glucuronosyl transferase, aldehyde-3-dehydrogenase, glutathione S-transferase Ya gene, and NAD(P)H:menadione oxidoreductase (1,35,53,56,62,64). Other studies also report that enhanced expression of other genes by TCDD is due to posttranscriptional processes (20).TCDD also decreases gene expression and/or the respective activities of the encoded proteins. Phosphoenolpyruvate carboxy kinase, glucose-6-phosphatase, and tryptophan 2,3-dioxygenase activities and mRNA levels are decreased in rats treated with an acutely toxic dose (125 g/kg of body weight) of TCDD (72). Rat uterine c-fos and epidermal growth factor * Corresponding author. Mailing address: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466.

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.

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