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Cholesterol is an important precursor of many endogenous molecules. Disruption of cholesterol homeostasis can cause many pathological changes, leading to liver and cardiovascular diseases. CYP1A is widely involved in cholesterol metabolic network, but its exact function has not been fully elucidated. Here, we aim to explore how CYP1A regulates cholesterol homeostasis. Our data showed that CYP1A1/2 knockout (KO) rats presented cholesterol deposition in blood and liver. The serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol were significantly increased in KO rats. Further studies found that the lipogenesis pathway (LXR α -SREBP1-SCD1) of KO rats was activated, and the key protein of cholesterol ester hydrolysis (CES1) was inhibited. Importantly, lansoprazole can significantly alleviate rat hepatic lipid deposition in hypercholesterolemia models by inducing CYP1A. Our findings reveal the role of CYP1A as a potential regulator of cholesterol homeostasis and provide a new perspective for the treatment of hypercholesterolemia., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Paris saponins, also known as polyphyllins, are natural compounds extracted from Paris polyphylla, which have many pharmacological activities, such as anti-inflammation and anti-cancer. In particular, paris saponin I, II, VII and polyphyllin VI are the components of the quality standard for Paris polyphylla. However, the inhibition risk of polyphyllins on cytochrome P450 (CYP) and UDP-glucuronosyltransferases (UGT) remains unclear. Therefore, this report investigated the potential inhibitory effects of paris saponin I, II, VII and polyphyllin VI on the activities of CYP (CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP2E1 and CYP3A2) and UGT (UGT1A1, UGT1A3, UGT1A6, PROG and AZTG) through cocktail inhibition assays in vitro. In the study of CYP, polyphyllin VI exhibited weak inhibition on CYP2D1 activity in rat liver microsomes with IC 50 value at 45.2 μM, while paris saponin VII weakly inhibited CYP2C11 and CYP2E1 activities with IC 50 value at 42.0 and 67.7 μM, respectively. In the study of UGT, none of the four steroidal saponins showed significant inhibition risk. In conclusion, paris saponin I, II, VII and polyphyllin VI have very low potential to cause the possible toxicity and drug interactions involving CYP and UGT enzymes, indicating that they are safe enough to take with drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)