Rat Urinary Bladder Carcinogenesis by Dual-Acting PPAR𝛼+𝛾 Agonists

Table 1

Frequency of cancer findings for PPAR agonists in rats, mice, and hamsters. The table is adapted from [8–10] and comprises rodent carcinogenicity data for between 16 and 30 PPARα agonists (pharmacological as well as industrial compounds) [9, 10], 5 PPARγ agonists (pharmacological compounds only) [8], and 6 dual-acting PPARα+γ agonists (pharmacological compounds only) [8]. Numbers in the cells: number of compounds causing the indicated pathology in the indicated rodent species; M: male; F: female. The difference in rodent bladder and liver tumour frequency between PPARα, PPARγ, and PPARα+γ agonists is significant (𝑃<.0001, Chi-square test). The difference in rodent bladder cancer frequency betwen PPARγ and dual-acting PPARα+γ agonists is borderline significant (𝑃=.0357 and .081 by Chi-square and Fischer’s exact tests, resp.).

^(a)PPAR agonist selectivity (𝑛, number of compounds)	^(b),(f)Hemangio-sarcoma	^(c),(f)Urinary bladder and renal pelvis	^(d)Fibrosarcoma	^(f)Lipoma and sarcoma	^(e),(f)Liver	Other
PPARα agonists (𝑛=30 for hepatocarcinogenicity, 𝑛=16 for extrahepatic tumours)	None	None	None	None	30 of 30, in mice or rats	Typically pancreatic acinar cell and Leydig cell tumours. Thyroid and lung tumours and leukaemia also described.
PPARγ agonists (𝑛=5)	3 (mice, M and F)	1 (rats, M and F)	None	3 (rats, M and F)	2 (rats and mice, F)	1 (mice, gallbladder adenoma). 1 (rats, stomach, leiomyosarcoma).
Dual acting PPARα+γ agonists (𝑛=6)	5 (mice, M and F, hamster, M)	5 (rats, M and F)	2 (rats, M and F)	2 (rats, mice, M and F)	3 (rats, mice, M and F)	1 (rats, testicular). 1 (rats, mammary). 1 (mice, mammary and stomach). 1 (rats, thyroid). 1 (rats, uterine). 1 (rats, uterine and leukaemia).

^(a)Comparative data for PPAR selectivity are lacking. No study has to our knowledge for a panel of PPAR agonists compared activity on all PPAR isoforms, between rats, mice, and humans, in the relevant cell type, for example, hepatocyte or urothelial. However, it is clear that selective PPARγ agonists may have significant PPARα activity [3, 5, 11].^(b) Mice appear to be more sensitive to the effect of PPARγ agonists than rats [12].^(c)Rat urothelium may be more sensitive to the carcinogenic effect of dual-acting PPARα+γ agonists than mouse urothelium. Bladder cancer was seen in SD, Wistar, and Fischer rats of both sexes [8]. Renal proximal tubular carcinoma was also observed with 2 dual agonists (undifferentiated sarcomatous tumours) [8].^(d)One dual-acting PPARα+γ agonist for which fibrosarcoma has been described is tesaglitazar [13].^(e)One PPARγ agonist for which hepatocarcinogenesis has been described is troglitazone [14].^(f)PPARα and PPARγ are typically described as having a tissue-restricted expression, with PPARβ expression being more ubiquitous [2, 15, 16]. Endothelial as well as urothelial cells coexpress PPARα and PPARγ isoforms [17–20]. White fat expresses mostly PPARγ [2, 15, 16], but it is increasingly recognized that PPARα may also have function in white fat [21]. Liver expresses mostly PPARα [2, 15, 16], but it is increasingly recognized that PPARγ may also have function in the liver [22–26].