Effects of major tanshinones isolated from Danshen (Salvia miltiorrhiza) on rat CYP1A2 expression and metabolism of model CYP1A2 probe substrates
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AbstractThis study explored the effects of Danshen on metabolism/pharmacokinetics of model CYP1A2 substrates and hepatic CYP1A2 expression in rats. The effects of Danshen and tanshinones on CYP1A2 activity was determined by metabolism of model substrates in vitro (phenacetin) and in vivo (caffeine). HPLC was used to determine model substrates/metabolites. The effect of Danshen on CYP1A2 expression was determined by Western blot. Tanshinones (1.25-50 mu M) competitively inhibited phenacetin O-deethylation in vitro. Inhibition kinetics studies showed the K(i) values were in the order: dihydrotanshinone (3.64 mu M), cryptotanshinone (4.07 mu M), tanshinone I (22.6 mu M) and tanshinone IIA (23.8 mu M), furafylline (35.8 mu M), a CYP1A2 inhibitor. The Ki of Danshen extract (mainly tanshinones) was 72 mu g/ml. Acute Danshen extract treatment (50-200 mg/kg, i.p.) decreased metabolism of caffeine to paraxanthine, with overall decrease in caffeine clearance (14-22%); increase in AUC (11-25%) and plasma T(1/2) (12-16%). Danshen treatment with (100 mg/kg/day, i.p. or 200 mg/kg/day, p.o.) for three or fourteen days showed similar pharmacokinetic changes of the CYP1A2 probe substrate without affecting CYP1A2 expression. This study demonstrated that major tanshinones competitively inhibited the metabolism of model CYP1A2 probe substrates but had no effect on rat CYP1A2 expression. (C) 2009 Elsevier GrnbH. All rights reserved.
All Author(s) ListWang X, Lee WYW, Or PMY, Yeung JHK
Journal namePhytomedicine
Year2009
Month8
Day1
Volume Number16
Issue Number8
PublisherELSEVIER GMBH, URBAN & FISCHER VERLAG
Pages712 - 725
ISSN0944-7113
eISSN1618-095X
LanguagesEnglish-United Kingdom
KeywordsCompetitive inhibition of CYP1A2 probes; CYP1A2; Danshen; Expression; Tanshinones
Web of Science Subject CategoriesChemistry, Medicinal; CHEMISTRY, MEDICINAL; Integrative & Complementary Medicine; INTEGRATIVE & COMPLEMENTARY MEDICINE; Pharmacology & Pharmacy; PHARMACOLOGY & PHARMACY; Plant Sciences; PLANT SCIENCES

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