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Numerous in vitro studies have shown that most pyrrolizidine alkaloids (PAs) are hepatotoxic after being metabolically activated by cytochrome P450 (CYP) 3A4. However, the key role of CYP3A4 has not been confirmed in vivo. Therefore, the CYP3A4 chemical inhibitor ritonavir was employed in this work and the effect of ritonavir on Gynura japonica-induced liver injury in rats was investigated. All experiments were approved by the Animal Research Committee of Shanghai University of Traditional Chinese Medicine. Animal welfare and the animal experimental protocols were strictly consistent with related ethics regulations of Shanghai University of Traditional Chinese Medicine. Acute liver injury was induced by a single gavage of Gynura japonica extracts (GJE, 8 g·kg-1); rats in the protection group were gavaged with ritonavir (RIT, 30 mg·kg-1) 1 h before GJE treatment. The results show that RIT could significantly attenuate GJE-induced liver injury in rats. Rats in the protection group showed decreased serum activities for alanine aminotransferase and aspartate aminotransferase, as well as lower total bile acids. In addition, the infiltration of inflammatory cells, sinusoidal hemorrhage, and hepatic necrosis in GJE-treated rats were markedly attenuated in the protection group. The content of pyrrole-protein adducts (PPAs), a recommended biomarker for PA-induced hepatotoxicity in clinics, was determined at 10 min to 24 h after GJE treatment. The content of 13 bile acids was also quantified. RIT treatment reduced the content of PPAs in serum dramatically and restored the impaired bile acid homeostasis caused by GJE. These studies indicate that RIT attenuated Gynura japonica-induced liver injury in rats, which was closely related to the inhibition of the metabolic activation of PAs and the regulation of bile acid metabolism. These results provide a better understanding of the relationship between CYP3A4 and PA-induced toxicity. This work will also be helpful in developing effective treatments for PA-induced liver injury and making a reasonable evaluation of the safety of drugs containing PAs in clinic.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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