Activation of CYP3A-mediated testosterone 6β-hydroxylation by tanshinone IIA and midazolam 1-hydroxylation by cryptotanshinone in human liver microsomes.
This study evaluated the in vitro activation of CYP3A-mediated midazolam 1-hydroxylation and testosterone 6β-hydroxylation by tanshinone I, tanshinone IIA, and cryptotanshinone. The abilities of tanshinones to activate CYP3A-mediated midazolam 1-hydroxylation and testosterone 6β-hydroxylation in human liver microsomes (HLMs) were tested. Substrate- and effector-dependent activation of CYP3A by tanshinones were both observed. Cryptotanshinone was shown to activate CYP3A-mediated midazolam 1-hydroxylation in a concentration-dependent manner. In contrast, tanshinone IIA and tanshinone I did not activate this hydroxylation reaction. In addition, tanshinone IIA activated CYP3A-mediated testosterone 6β-hydroxylation, whereas cryptotanshinone and tanshinone I did not. The results from our study enhance the understanding of CYP3A activation by tanshinone IIA and cryptotanshinone in HLMs. Additionally, these data allow for an accurate prediction of the magnitude and likelihood of Danshen-drug interactions.
Lab of Clinical Pharmacokinetics, Shuguang hospital, Shanghai University of Traditional Chinese Medicine, China.
Furong
F
Qiu
Rong
R
Zhang
Guangji
G
Wang
Chenglu
C
Gao
Jianguo
J
Sun
Jian
J
Jiang
Yueming
Y
Ma
D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D006915:Hydroxytestosterones / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D008874:Midazolam / Q000494:pharmacology*; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D013739:Testosterone / Q000378:metabolism*
D045784:Abietanes; D006915:Hydroxytestosterones; D010616:Phenanthrenes; C021751:tanshinone; D013739:Testosterone; C037886:cryptotanshinone; C025591:6 beta-hydroxytestosterone; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam