Table 2.
Examples of chemical-, gender-, species-, and PPARα polymorphism-dependent responses to PPARα agonists.a
| Parameter | Test subjects | WY | DBP | GEM | DEHP |
|---|---|---|---|---|---|
| NADPH–CYP oxidoreductase | |||||
| mRNA | F-344 male rat | ↑ 4.4-fold | ↑ 2.2-fold | No change | — |
| F-344 female rat | ↑ 7.2-fold | ↑ 5.1-fold | ↑ 4.4-fold | — | |
| Wild-type male mouse | ↑ 4.6-fold | — | — | ↑ 5.8-fold | |
| PPARα null male mouse | No change | — | — | No change | |
| Protein | F-344 male rat | ↓ to 29% | No change | ↓ to 18% | — |
| F-344 female rat | No change | ↑ 3.2-fold | No change | — | |
| SD male rat | ↓ to 40% | — | ↓ to 14% | — | |
| Wild-type male mouse | ↓ to 4% | — | — | ↓ to 12% | |
| PPARα null male mouse | No change | — | — | ↑ 2.0-fold | |
| Nonspecific carboxyesterase proteinb | |||||
| ES-4 | F-344 male rat | ↓ to 30% | No change | ↓ to 15% | — |
| F-344 female rat | No change | No change | ↑ 1.6-fold | — | |
| SD male rat (#1) | ↓ to 12% | ↓ to 39% | ↓ to 32% | — | |
| SD male rat (#2) | ↓ to 13% | ↓ to 63% | ↓ to 16% | — | |
| Wild-type male mouse | No change | — | — | No change | |
| PPARα male null mouse | No change | — | — | No change | |
| ES-10 | F-344 male rat | ↓ to 1% | No change | ↓ to 10% | — |
| F-344 female rat | ↓ to 10% | ↑ 2.0-fold | No change | — | |
| SD male rat (#1) | ↓ to 7% | ↓ to 59% | ↓ to 16% | — | |
| SD male rat (#2) | ↓ to 8% | ↓ to 60% | ↑ 1.4-fold | — | |
| Wild-type male mouse | No change | — | — | No change | |
| PPARα null male mouse | No change | — | — | ↓ to 50% | |
| 2α-Testosterone hydroxylase activity | F-344 male rat | ↓ to < 1% | ↓ to 43% | ↓ to 31% | — |
| 6β-Testosterone hydroxylase activity | F-344 male rat | No change | ↑ 2.6-fold | ↑ 2.0-fold | — |
| 7α-Testosterone hydroxylase activity | F-344 male rat | No change | No change | No change | — |
| 16α-Testosterone hydroxylase activity | F-344 male rat | ↓ to 4% | ↓ to 47% | ↓ to 35% | — |
| 16β-Testosterone hydroxylase activity | F-344 male rat | ↑ 2.3-fold | ↑ 3.2-fold | ↑ 3.6-fold | — |
| Androstenedione hydroxylase activity | F-344 male rat | ↓ to 24% | No change | No change | — |
| CYP3A11 mRNA (6α-testoserone hydroxylase) | Wild-type male mouse | ↓ to 40% | — | — | ↑ 5.7-fold |
| PPARα null male mouse | ↑ 1.9-fold | — | — | ↑ 5.7-fold | |
| CYP3A2 mRNA | F-344 male rat | ↓ to 25% | No change | ↓ to 36% | — |
| CYP3A2 proteinb | F-344 male rat | ↓ to 13% | ↑ 1.9-fold | No change | — |
| F-344 female rat | No change | ↑ 5.0-fold | ↑ 5.0-fold | — | |
| SD male rat (#1) | ↓ to 15% | ↓ to 57% | No change | — | |
| SD male rat (#2) | ↓ to 3% | No change | No change | — | |
| CYP3A1 protein | F-344 male rat | ↑ 11-fold | ↑ 15-fold | ↑ 2-fold | — |
| F-344 female rat | ↓ to 42% | ↑ 4.6-fold | ↓ to 50% | — | |
| CYP2B1 protein | F-344 male rat | No change | ↑ 2.4-fold | No change | — |
| F-344 female rat | No change | ↑ 8.0-fold | ↑ 3.9-fold | — | |
| CYP4A protein | F-344 male rat | ↑ > 80-fold | ↑ > 60-fold | ↑ > 16-fold | — |
| F-344 female rat | ↑ 60-fold | No change | No change | — | |
| Estrogen sulfotransferase protein | F-344 male rat | ↓ to 2% | ↓ to 8% | ↓ to12% | — |
| F-344 female ratc | ↓ | ↓ | ↓ | — | |
| Glutathione S-transferased | SD male rat | ↓ to 11% | ↓ to 43% | No change | — |
| Selenium-dependent glutathione peroxidased | SD male rat | ↓ to 66% | ↓ to 76% | No change | — |
| Glutathione equivalentsd | SD male rat | No change | ↓ to 66% | No change | — |
Abbreviations: —, not tested; ↑, increased; ↓, decreased; DBP, dibutyl phthalate; SD, Sprague-Dawley.
Results are from Poole et al. (2001), Fan et al. (2003, 2004), and O’Brien et al. (2001) in which F-344 rats, Sprague-Dawley rats, or SV129 PPARα (+/+) or (−/−) “null” or “knockout” mice were exposed for 13 (rats) or 3 (mice) weeks. Rats received control diet, 500 ppm WY, 8,000 ppm GEM, or 20,000 ppm dibutyl phthalate in the diet. Mice received control diet, 0.1% WY, or 0.6% DEHP in diet.
Results from Fan et al. (2004) and Poole et al. (2001) included two sets of experiments for Sprague-Dawley rats.
No quantitative number given but reported to be statistically significant. Testosterone hydroxylase activities are derived from hepatic microsomes.
Exposure level of GEM is 16,000 ppm. Parameters investigated in the liver include NADPH–CYP oxidoreductase, an often rate-limiting component in CYP-dependent reactions; nonspecific carboxyesterases, a large group of enzymes that play important roles in the metabolism of endogenous lipids and foreign compounds such as pesticides and drugs; phase I and II steroid metabolism enzymes; and glutathione and glutathione-related enzyme activities.