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<p>The increasing use of natural product-based supplements or medicines alongside prescription drugs carries risks of metabolic interference, potentially leading to toxicity or reduced therapeutic efficacy. However, the inhibitory activity of many natural compounds has not been comprehensively evaluated. Here, we investigated the potential in vitro inhibitory effects of 39 natural compounds on cytochrome P450 (CYP) enzymes via inhibition and kinetic analyses using pooled human liver microsomes. Based on screening at compound concentrations of 10&#xa0;μM, α-cyperone and evodiamine showed weak inhibition of CYP2C19 (IC<sub>50</sub> &gt; 10&#xa0;μM), aloe-emodin, emodin, and isoimperatorin showed moderate inhibition of CYP1A2 (IC<sub>50</sub> 1–10&#xa0;μM), and bergapten, imperatorin, and xanthotoxin showed potent inhibition of CYP1A2 (IC<sub>50</sub> &lt; 1&#xa0;μM). Notably, bergapten and xanthotoxin exhibited metabolism-dependent inhibition, implying the potential for mechanism-based inactivation. Kinetic analysis demonstrated that aloe-emodin inhibited CYP1A2 via a mixed-type mechanism (K<sub>i</sub> = 0.6&#xa0;μM), reflecting relatively selective inhibition. Structural characteristics were the major determinants of CYP inhibitory properties: furanocoumarins acted as strong or metabolism-dependent inhibitors, whereas anthraquinones exerted selective and reversible inhibitory effects on CYP1A2. Aloe-emodin showed potential as a relatively selective reversible inhibitor for mechanistic studies of CYP1A2-mediated drug metabolism. Based on reported human plasma C<sub>max</sub> values, the estimated [I]/IC₅₀ ratios for bergapten (0.55–1.38) and xanthotoxin (0.45–2.27) suggest a potential risk of clinically relevant CYP1A2-mediated herb–drug interactions. Our findings highlight the value of combining in vitro inhibition data with pharmacokinetic considerations when evaluating the interaction risks of natural products.</p>

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In vitro study of inhibitory effects on cytochrome P450 by thirty-nine natural products with pharmacological activities

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • Chae Heon Lim,
  • Jieun Yu,
  • Jang Su Jeon,
  • Sang Kyum Kim

摘要

The increasing use of natural product-based supplements or medicines alongside prescription drugs carries risks of metabolic interference, potentially leading to toxicity or reduced therapeutic efficacy. However, the inhibitory activity of many natural compounds has not been comprehensively evaluated. Here, we investigated the potential in vitro inhibitory effects of 39 natural compounds on cytochrome P450 (CYP) enzymes via inhibition and kinetic analyses using pooled human liver microsomes. Based on screening at compound concentrations of 10 μM, α-cyperone and evodiamine showed weak inhibition of CYP2C19 (IC50 > 10 μM), aloe-emodin, emodin, and isoimperatorin showed moderate inhibition of CYP1A2 (IC50 1–10 μM), and bergapten, imperatorin, and xanthotoxin showed potent inhibition of CYP1A2 (IC50 < 1 μM). Notably, bergapten and xanthotoxin exhibited metabolism-dependent inhibition, implying the potential for mechanism-based inactivation. Kinetic analysis demonstrated that aloe-emodin inhibited CYP1A2 via a mixed-type mechanism (Ki = 0.6 μM), reflecting relatively selective inhibition. Structural characteristics were the major determinants of CYP inhibitory properties: furanocoumarins acted as strong or metabolism-dependent inhibitors, whereas anthraquinones exerted selective and reversible inhibitory effects on CYP1A2. Aloe-emodin showed potential as a relatively selective reversible inhibitor for mechanistic studies of CYP1A2-mediated drug metabolism. Based on reported human plasma Cmax values, the estimated [I]/IC₅₀ ratios for bergapten (0.55–1.38) and xanthotoxin (0.45–2.27) suggest a potential risk of clinically relevant CYP1A2-mediated herb–drug interactions. Our findings highlight the value of combining in vitro inhibition data with pharmacokinetic considerations when evaluating the interaction risks of natural products.