TY - JOUR
T1 - Investigation of cytochrome P450 inhibitory properties of deoxyshikonin, a bioactive compound from Lithospermum erythrorhizon Sieb. et Zucc
AU - Zhang, Yuanjin
AU - Gao, Jing
AU - Xu, Yuan
AU - Liu, Jie
AU - Huang, Shengbo
AU - Li, Guihong
AU - Yao, Bingyi
AU - Sun, Zhenliang
AU - Wang, Xin
N1 - Publisher Copyright:
© 2022 John Wiley & Sons Ltd.
PY - 2024/10
Y1 - 2024/10
N2 - Deoxyshikonin, a natural naphthoquinone compound extracted from Lithospermum erythrorhizon Sieb. et Zucc (Boraginaceae), has a wide range of pharmacological activities, including anti-tumor, anti-bacterial and wound healing effects. However, the inhibitory effect of deoxyshikonin on cytochrome P450 (CYP) remains unclear. This study investigated the potential inhibitory effects of deoxyshikonin on CYP1A2, 2B1/6, 2C9/11, 2D1/6, 2E1 and 3A2/4 enzymes in human and rat liver microsomes (HLMs and RLMs) by the cocktail approach in vitro. The single-point inactivation experiment showed that deoxyshikonin presented no time-dependent inhibition on CYP activities in HLMs and RLMs. Enzyme inhibition kinetics indicated that in HLMs, deoxyshikonin was not only a competitive inhibitor of CYP1A2 and 2E1, but also a mixed inhibitor of CYP2B6, 2C9, 2D6 and 3A4, with Ki of 2.21, 1.78, 1.68, 0.20, 4.08 and 0.44 μM, respectively. In RLMs, deoxyshikonin not only competitively inhibited CYP2B1 and 2E1, but also exhibited mixed inhibition on CYP1A2, 2C11, 2D1 and 3A2, with Ki values of no more than 18.66 μM. In conclusion, due to the low Ki values of deoxythiokonin on CYP enzymes in HLMs, this may lead to drug–drug interactions (DDI) and potential toxicity.
AB - Deoxyshikonin, a natural naphthoquinone compound extracted from Lithospermum erythrorhizon Sieb. et Zucc (Boraginaceae), has a wide range of pharmacological activities, including anti-tumor, anti-bacterial and wound healing effects. However, the inhibitory effect of deoxyshikonin on cytochrome P450 (CYP) remains unclear. This study investigated the potential inhibitory effects of deoxyshikonin on CYP1A2, 2B1/6, 2C9/11, 2D1/6, 2E1 and 3A2/4 enzymes in human and rat liver microsomes (HLMs and RLMs) by the cocktail approach in vitro. The single-point inactivation experiment showed that deoxyshikonin presented no time-dependent inhibition on CYP activities in HLMs and RLMs. Enzyme inhibition kinetics indicated that in HLMs, deoxyshikonin was not only a competitive inhibitor of CYP1A2 and 2E1, but also a mixed inhibitor of CYP2B6, 2C9, 2D6 and 3A4, with Ki of 2.21, 1.78, 1.68, 0.20, 4.08 and 0.44 μM, respectively. In RLMs, deoxyshikonin not only competitively inhibited CYP2B1 and 2E1, but also exhibited mixed inhibition on CYP1A2, 2C11, 2D1 and 3A2, with Ki values of no more than 18.66 μM. In conclusion, due to the low Ki values of deoxythiokonin on CYP enzymes in HLMs, this may lead to drug–drug interactions (DDI) and potential toxicity.
KW - cocktail approach
KW - cytochrome P450 (CYP)
KW - deoxyshikonin
KW - drug–drug interactions (DDI)
KW - enzyme inhibition kinetics
UR - https://www.scopus.com/pages/publications/85141422968
U2 - 10.1002/ptr.7664
DO - 10.1002/ptr.7664
M3 - 文章
C2 - 36317387
AN - SCOPUS:85141422968
SN - 0951-418X
VL - 38
SP - 4855
EP - 4864
JO - Phytotherapy Research
JF - Phytotherapy Research
IS - 10
ER -