title: Effects of major tanshinones isolated from Danshen (Salvia miltiorrhiza) on rat CYP1A2 expression and metabolism of model CYP1A2 probe substrates.
abstract: This 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 microM) competitively inhibited phenacetin O-deethylation in vitro. Inhibition kinetics studies showed the K(i) values were in the order: dihydrotanshinone (3.64 microM), cryptotanshinone (4.07 microM), tanshinone I (22.6 microM) and tanshinone IIA (23.8 microM), furafylline (35.8 microM), a CYP1A2 inhibitor. The Ki of Danshen extract (mainly tanshinones) was 72 microg/ml. Acute Danshen extract treatment (50-200mg/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 (100mg/kg/day, i.p. or 200mg/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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Wayne Y W
authors.initials: WY
authors.lastname: Lee
authors.forename: Penelope M Y
authors.initials: PM
authors.lastname: Or
authors.forename: John H K
authors.initials: JH
authors.lastname: Yeung
mesh_terms: D045784:Abietanes; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000302:isolation & purification / Q000494:pharmacology*; D019540:Area Under Curve; D002110:Caffeine / Q000493:pharmacokinetics; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006207:Half-Life; D008297:Male; D008657:Metabolic Clearance Rate; D010615:Phenacetin / Q000493:pharmacokinetics; D010616:Phenanthrenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D018517:Plant Roots; D010946:Plants, Medicinal / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D027561:Salvia miltiorrhiza / Q000737:chemistry*
chemical_list: D045784:Abietanes; D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000697:Central Nervous System Stimulants; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; D010618:Phenanthrolines; D010936:Plant Extracts; C021751:tanshinone; C028972:dan-shen root extract; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2; D010615:Phenacetin