Pulmonary Toxicity and Metabolic Activation of Dauricine in CD-1 Mice

Abstract

Dauricine is the major bioactive component isolated from the roots of Menispermum dauricum D.C. and has shown promising pharmacological activities with a great potential for clinic use. However, the adverse effects and toxicity of the alkaloid are unfortunately ignored. The objective of the current study was to evaluate the toxicity of dauricine in vitro and in vivo. Mice (CD-1) were treated intraperitoneally with dauricine at various doses, and sera and lung lavage fluids were collected after 24 h of treatment. No changes in serum aspartate aminotransferase, alanine aminotransferase, and blood urea nitrogen were noticed, whereas a dose-dependent increase in lactate dehydrogenase activity was observed in lung lavage fluids. Ethidium-based staining studies showed that remarkable cells lost membrane integrity in the lungs of the animals treated with dauricine at 150 mg/kg. Histopathological evaluation of lungs of mice showed that dauricine at the same dose caused significant alveolar edema and hemorrhage. Exposure to dauricine at 40 M for 24 h resulted in up to 60% cell death in human lung cell lines BEAS-2B, WI-38, and A549. Ketoconazole showed protective effect on the pulmonary injury in mice given dauricine. A quinone methide metabolite of dauricine was identified in mouse lung microsomal incubations, and the presence of ketoconazole in the microsomal incubations suppressed the formation of the quinone methide metabolite. In conclusion, dauricine produced pulmonary injury in CD-1 mice. The pulmonary toxicity appears to depend on the metabolism of dauricine mediated by CYP3A. The electrophilic quinone methide metabolite probably plays an important role in the pulmonary toxicity induced by dauricine.

Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-κB ligand–induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca2+–nuclear factor of activated T-cells cytoplasmic 1 signaling pathways

“…The effects of CADPE in bone homeostasis are similar to the widely used osteoporosis drugs, bisphosphonates, which also inhibit bone digestion by osteoclasts and stimulate the formation of osteoblast precursors. (43) Therefore, further investigation will be needed to understand the mechanism of CADPE's involvement in osteoblast differentiation.…”

N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca2+ Mobilization

“…In this study, we used a derivative of dauricine ( N -desmethyldauricine/LP-4) to further verify the precise cellular machinery regulating the autophagic cell death. Derivatives of dauricine are of interest since dauricine has been shown in vitro to process anti-cancer property in colon (Yang et al, 2010), lung (Jin et al, 2010), breast (Tang et al, 2009), and urinary cancers (Wang et al, 2012). In fact, our previous findings point toward potential use of dauricine in multidrug- and apoptosis-resistant cancers intervention (Law et al, 2014).…”

“…For example, we previously found that, dauricine induced autophagic cell death with a higher IC 50 value (Law et al, 2014) toward the cell lines MCF-7 (28.7 μM) and A549 (40.4 μM), while the IC 50 value corresponding to these cell lines upon LP-4 treatment are 1.8 to 2-fold lower as demonstrated in this report: MCF-7 (15.5 μM) and A549 (19.7 μM). Such higher cytotoxicity could be a result of the existence of the electrophilic quinone methide group on LP-4 (Wang et al, 2009; Jin et al, 2010). However, the molecular mechanisms for inducing the higher cellular toxicity as demonstrated might be attributed to increased autophagic effect (unpublished observation).…”

“…Dauricine, the major bioactive alkaloid isolated from Menispermum dauricum D.C. (Jin et al, 2010), has been widely prescribed to treat inflammatory diseases (Yang et al, 2010), allergy, and arrhythmia in the local Chinese community. The reported pharmacological effect of dauricine has been attributed to its anti-arrhythmic effect and the ability to modulate Ca 2+ and several K + channels.…”

Bioactivation of herbal constituents: simple alerts in the complex system

“…It has been reported that para-methylene phenol moiety in dauricine underwent CYP3A4-mediated bioactivation to generate a quinone methide reactive intermediate, which was trapped with nucleophilic agents such as reduced glutathione [73]. The reactive quinone methide intermediate plays a dominant role in pulmonary toxicity induced by dauricine in CD-1 mice [74].…”