Journal of ethnopharmacology · 2026
Inhibitory effects and molecular mechanisms of Aristolochic acids on human and rat placental 3β-hydroxysteroid dehydrogenases.
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Yang Yuli, Ren Xiya, Gong Chaochao, Wang Lingfei, Chen Zhuoqi, Tang Yunbing, Ge Ren-Shan, Ying Yingfen
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: "Mutong" (commonly known as Akebiae Caulis), historically referring to a group of herbal medicines derived from multiple botanical origins, has been employed in traditional Chinese medicine for over 2000 years and remains in widespread use today. In recent decades, certain species of Akebiae Caulis (particularly Aristolochiaceae family) have been reported to exhibit significant toxicity.
AIM OF THE STUDY: The objectives of the current study are to investigate phytochemical Aristolochic acids (AAs) derived from Aristolochiaceae species, focusing on their inhibitory effects on placental 3β-hydroxysteroid dehydrogenase (3β-HSD) and to explore their mechanisms, thereby contributing to understanding their pharmacological and toxicological profiles.
METHODS: In vitro enzyme activity assays were conducted to evaluate the inhibitory potential of seven AAs (including AA-I to AA-IVa, aristolone, and 7-hydroxyaristolochic acid) on human 3β-HSD1/rat 3β-HSD4, determining IC50 and Kᵢ values and cellular inhibition potency in JAr cells. The mode of inhibition was studied through enzyme kinetics, while molecular binding interactions were simulated using Autodock. Additionally, network toxicology analysis was performed to assess toxicological relevance.
RESULTS: AA-II, AA-IIIa, aristolone, and 7-hydroxyaristolochic acid demonstrated significant inhibition of both human 3β-HSD1 and rat 3β-HSD4. The IC50 values against human 3β-HSD1 ranged from 14.68 μM (AA-II) to 187.69 μM (7-hydroxyaristolochic acid), with a similar inhibitory potency trend observed against 3β-HSD4. Kinetic analysis indicated mixed/noncompetitive inhibition. Molecular docking simulations revealed that AAs bind at the steroid/NAD+ interface or NAD+ binding site. Network toxicology analysis further associated AAs with adverse outcomes such as fetal growth restriction and renal cell carcinoma, primarily through disruption of steroid hormone synthesis and nuclear receptor signaling pathways.
CONCLUSIONS: AAs act as strong inhibitors of placental 3β-HSD, exhibiting mixed/noncompetitive inhibition. Their association with risks of fetal growth restriction and renal cell carcinoma highlights significant toxicological concerns that warrant further attention.
AIM OF THE STUDY: The objectives of the current study are to investigate phytochemical Aristolochic acids (AAs) derived from Aristolochiaceae species, focusing on their inhibitory effects on placental 3β-hydroxysteroid dehydrogenase (3β-HSD) and to explore their mechanisms, thereby contributing to understanding their pharmacological and toxicological profiles.
METHODS: In vitro enzyme activity assays were conducted to evaluate the inhibitory potential of seven AAs (including AA-I to AA-IVa, aristolone, and 7-hydroxyaristolochic acid) on human 3β-HSD1/rat 3β-HSD4, determining IC50 and Kᵢ values and cellular inhibition potency in JAr cells. The mode of inhibition was studied through enzyme kinetics, while molecular binding interactions were simulated using Autodock. Additionally, network toxicology analysis was performed to assess toxicological relevance.
RESULTS: AA-II, AA-IIIa, aristolone, and 7-hydroxyaristolochic acid demonstrated significant inhibition of both human 3β-HSD1 and rat 3β-HSD4. The IC50 values against human 3β-HSD1 ranged from 14.68 μM (AA-II) to 187.69 μM (7-hydroxyaristolochic acid), with a similar inhibitory potency trend observed against 3β-HSD4. Kinetic analysis indicated mixed/noncompetitive inhibition. Molecular docking simulations revealed that AAs bind at the steroid/NAD+ interface or NAD+ binding site. Network toxicology analysis further associated AAs with adverse outcomes such as fetal growth restriction and renal cell carcinoma, primarily through disruption of steroid hormone synthesis and nuclear receptor signaling pathways.
CONCLUSIONS: AAs act as strong inhibitors of placental 3β-HSD, exhibiting mixed/noncompetitive inhibition. Their association with risks of fetal growth restriction and renal cell carcinoma highlights significant toxicological concerns that warrant further attention.