Triptolide-induced hepatotoxicity can be alleviated when combined with Panax notoginseng saponins and Catapol

Abstract

Ethnopharmacological relevance: The hepatotoxicity of Tripterygium wilfordii Hook. f. (TW), due to the presence of triptolide (TP), limits its therapeutic potential. Based on the traditional Chinese medicine theory, the theory of "Yi lei xiang zhi" was proposed that Chinese herbs with different efficacy can restrict each other to achieve the least adverse reactions.

Aim of the study: To observe the effects of Catapol (CAT) and Panax notoginseng saponins (PNS), active ingredients in Rehmannia glutinosa (RG) and Panax notoginseng (PN) respectively, on reducing TP-induced hepatotoxicity, and further to explore the mechanisms.

Materials and methods: The human hepatic cell line L-02 was cultured and treated with CAT, PNS or Combinations, and then treated with TP. The cytotoxic assay, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), apoptosis, mitochondrial membrane potential and the expressions of NF-E2-related factor 1 (Nrf1) and its downstream targets were detected. Rats were treated with TP, TP + CAT, TP + PNS, or the combinations for 4 weeks. The levels of ALT, AST and LDH in serum, apoptosis of liver cells, mitochondria injury and the protein expressions of Caspase 3 and Nrf1 were investigated.

Results: CAT, PNS or CAT+PNS pre-treatment inhibited TP-induced toxicity in L-02 cells, distinctly decreased the apoptosis, alleviated the reduction of mitochondrial membrane potential, and modulated the expressions of Nrf1 and its downstream target, the mitochondrial transcription factor A (TFAM) and cytochrome C (Cyt-C). CAT, PNS or CAT+PNS inhibited the TP-induced hepatotoxicity in SD rats by reducing the mitochondria injury, decreasing the cells apoptosis and increasing the Nrf1 protein expression. Noticeably, TP + PNS + CAT combinations exhibited more effective than any single ingredient alone.

Conclusion: PNS and CAT were able to effectively attenuate TP-induced hepatotoxicity. The efficiency benefits from their modulating Nrf1 and its downstream genes TFAM and Cyt-C, and further influencing mitochondrial functions and cells apoptosis. The combination is more effective than single ingredient alone.

Keywords: Catapol; Catapol (PubChem CID:24721265); Hepatotoxicity; Mitochondria; Nrf1; Panax notoginseng saponins; Panax notoginseng saponins (PubChem CID:441934); Triptolide; Triptolide (PubChem CID:107985).