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ABSTRACT: Previous studies have shown that major tanshinones isolated from Danshen (Salvia miltiorrhiza) inhibited human and rat CYP450 enzymes-mediated metabolism of model probe substrates, with potential in causing herb-drug interactions. Miltirone, another abietane type-diterpene quinone isolated from Danshen, has been reported for its anti-oxidative, anxiolytic and anti-cancer effects. The aim of this study was to study the effect of miltirone on the metabolism of model probe substrates of CYP1A2, 2C9, 2D6 and 3A4 in pooled human liver microsomes. Miltirone showed moderate inhibition on CYP1A2 (IC(50)=1.73μM) and CYP2C9 (IC(50)=8.61μM), and weak inhibition on CYP2D6 (IC(50)=30.20μM) and CYP3A4 (IC(50)=33.88μM). Enzyme kinetic studies showed that miltirone competitively inhibited CYP2C9 (K(i)=1.48μM), and displayed mixed type inhibitions on CYP1A2, CYP2D6 and CYP3A4 with K(i) values of 3.17μM, 24.25μM and 35.09μM, respectively. Molecular docking study further confirmed the ligand-binding conformations of miltirone in the active sites of these human CYP450 isoforms, and provided some information on structure-activity relationships for the CYPs inhibition by tanshinones. Taken together, CYPs inhibitions of miltirone were weaker than dihydrotanshinone, but stronger than cryptotanshinone, tanshinone I and tanshinone IIA.
Phytomedicine: international journal of phytotherapy and phytopharmacology 10/2012; · 2.17 Impact Factor
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Xuelin Zhou,
Shun Wan Chan,
Hui Ling Tseng,
Yan Deng,
Pui Man Hoi,
Pou Seng Choi,
Penelope M Y Or,
Jia-Ming Yang,
Francis F Y Lam,
Simon Ming Yuen Lee,
George Pak Heng Leung,
Siu Kai Kong,
Ho Pui Ho,
Yiu Wa Kwan, John H K Yeung
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ABSTRACT: Some of the major components of Danshen (Salvia miltiorrhiza), a widely used Chinese herbal medicine rich in phenolic acids, are thermosensitive and may degrade to other phenolic acids during extractions with heating. The chemical profiles of Danshen water-extract may vary with different heat water extraction at different temperatures, affecting the composition and bioactivity of the extracts. In this study, six water-extracts of Danshen obtained from heat reflux water extraction and microwave-assisted extraction with water (MAE-W) at different temperatures were tested for their composition and pharmacological effects. Among these extracts, the third-round MAE-W (100°C) extract had the highest phenolic acids and tanshinones contents, with the strongest antioxidant activity in 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay and ferric reducing/antioxidant potential (FRAP) assay. This extract also showed the strongest inhibitory effects on 2,2'-azobis-2-amidinopropane (AAPH)-induced hemolysis in human red blood cells, hydrogen peroxide-induced apoptosis in rat heart H9c2 cells and the highest relaxation effects on rat basilar artery. The antioxidant effects of Danshen water-extracts linearly correlated to their relaxation effects (r=0.895-0.977). Through multiple linear regression analysis, danshensu was found to be the most significant marker in the antioxidant and vasodilation effects of Danshen water-extract, while tanshinone IIA as the marker on hydrogen peroxide-induced apoptosis in rat heart H9c2 cells. Danshensu is, therefore, a useful marker for the quality control of Danshen water-extracts in antioxidant and vasodilation, while tanshinone IIA for anti-apoptotic potential of different extracts.
Phytomedicine: international journal of phytotherapy and phytopharmacology 09/2012; · 2.17 Impact Factor
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Ru Feng,
Xuelin Zhou,
Penelope M Y Or,
Jing-Yi Ma,
Xiang-Shan Tan,
Jie Fu,
Chao Ma,
Jian-Gong Shi,
Chun-Tao Che,
Yan Wang, John H K Yeung
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ABSTRACT: Halenia elliptica D. Don is a Tibetan herb and medicinal preparations containing Halenia elliptica have been commonly used for the treatment of hepatitis B virus infection in China. The metabolism of 1-hydroxy-2,3,5-trimethoxy-xanthone (HM-1) to its metabolites is mediated through cytochrome P450 enzymes. This study aimed to investigate the herb-drug interaction potential of HM-1 by studying its effects on the metabolism of model probe substrates of five major CYP450 isoforms in human liver microsomes. HM-1 showed moderate inhibitory effects on CYP1A2 (IC(50)=1.06μM) and CYP2C9 (IC(50)=3.89μM), minimal inhibition on CYP3A4 (IC(20)=11.94μM), but no inhibition on model CYP2D6 (dextromethorphan) and CYP2E1 (chlorzoxazone) probe substrates. Inhibition kinetic studies showed that the K(i) values of HM-1 on CYP1A2, CYP2C9 and CYP3A4 were 5.12μM, 2.00μM and 95.03μM, respectively. HM-1 competitively inhibited testosterone 6β-hydroxylation (CYP3A4) but displayed mixed type inhibitions for phenacetin O-deethylation (CYP1A2) and tolbutamide 4-hydroxylation (CYP2C9). Molecular docking study confirmed the inhibition modes of HM-1 on these human CYP isoforms.
Phytomedicine: international journal of phytotherapy and phytopharmacology 07/2012; 19(12):1125-33. · 2.17 Impact Factor
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Ru Feng,
Yi-Ying Zhang,
Xi Chen,
Yan Wang,
Jian-Gong Shi,
Chun-Tao Che, John H K Yeung,
Jing-Yi Ma,
Xiang-Shan Tan,
Chen Yang,
Yu-Lin Deng,
Yu-Kui Zhang
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ABSTRACT: The metabolisms of five xanthones isolated from a Tibetan medicinal herb Halenia elliptica D. Don, including 1-hydroxy-2,3,5-trimethoxy-xanthone (HM-1), 1-hydroxy-2,3,4,7-tetramethoxy-xanthone (HM-2), 1-hydroxy-2,3,4,5-tetramethoxy-xanthone (HM-3), 1,7-dihydroxy-2,3,4,5-tetramethoxy-xanthone (HM-4) and 1,5-dihydroxy-2,3-dimethoxy-xanthone (HM-5), were studied in rat liver microsomes in vitro. High performance liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LC-ESI-IT-TOF) was applied for identification of metabolites of five xanthones mentioned above and (1)H NMR was used to elucidate the major metabolites. The structures of thirteen metabolites were identified and seven of them had not been reported before. Moreover, xanthone isomers herein could be distinguished by difference of fragmentation behaviors with increase of stages or relative abundances. The results indicated that in vitro metabolic transformation of HM-1, HM-2, HM-3, HM-4 and HM-5 occurred mainly at 2-, 4-, 5-, 7-carbonic positions on their structures of parent drugs. The metabolites could be new vasoactive substances. This work will provide a basis for study on the structure-activity relationships of these xanthones and their derivatives from Tibetan herbal in the next work.
Journal of pharmaceutical and biomedical analysis 03/2012; 62:228-34. · 2.45 Impact Factor
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ABSTRACT: Polysaccharide peptide (PSP), isolated from COV-1 strain of Coriolus versicolor, is commonly used as an adjunct in cancer chemotherapy or health supplement in China. Previous studies have shown that PSP decreased antipyrine clearance and inhibited rat CYP2C11-mediated tolbutamide 4-hydroxylation and in human CYP2C9. In this study, the effects of the water extractable fraction of PSP on the metabolism of model CYP1A2, CYP2D6, CYP2E1 and CYP3A4 probe substrates were investigated in pooled human liver microsomes. PSP (1.25-20μM) dose-dependently decreased CYP1A2-mediated metabolism of phenacetin to paracetamol (IC(50) 19.7μM) and CYP3A4-mediated metabolism of testosterone to 6β-hydroxytestosterone (IC(20) 7.06μM). Enzyme kinetics studies showed the inhibition of CYP1A2 activity was competitive and concentration-dependent (K(i)=18.4μM). Inhibition of testosterone to 6β-hydroxytestosterone was also competitive and concentration-dependent (K(i)=31.8μM). Metabolism of dextromethorphan to dextrorphan (CYP2D6-mediated) and chlorzoxazone to 6-hydroxychlorzoxazone (CYP2E1-mediated) was only minimally inhibited by PSP, with IC(20) values at 15.6μM and 11.9μM, respectively. This study demonstrated that PSP competitively inhibited the CYP1A2- and CYP3A4-mediated metabolism of model probe substrates in human liver microsomes in vitro. The relatively high K(i) values for CYP1A2 and CYP3A4 would suggest a low potential for PSP to cause herb-drug interaction related to these CYP isoforms.
Phytomedicine: international journal of phytotherapy and phytopharmacology 03/2012; 19(5):457-63. · 2.17 Impact Factor
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ABSTRACT: Visceral hypersensitivity is an important characteristic feature of functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). This study evaluated the effect of Schisandra chinensis on visceral hyperalgesia induced by neonatal maternal separation (NMS) in an IBS rat model. The visceromotor responses to colorectal balloon distension (CRD) were measured by abdominal withdrawal reflex (AWR) and electromyographic (EMG) activities. NMS control rats (receiving vehicle) underwent aggravated visceral pain in response to CRD as compared to normal rats, evidenced by the reduced pain threshold, enhanced AWR scores and EMG responses. Treatment with a 70% ethanol extract of S. chinensis (0.3g/kg and 1.5g/kg/day) for 7 days resulted in an increase in the pain threshold (NMS control: 19.1±1.0mmHg vs low-dose: 24.8±1.3mmHg and high-dose: 25.2±1.8mmHg, p<0.01), and abolished the elevated AWR and EMG responses to CRD in NMS rats (AUC values of EMG response curve were: 1952±202 in NMS control group vs 1074±90 in low-dose group and 1145±92 in high-dose group, p<0.001), indicating that S. chinensis could reverse the visceral hypersensitivity induced by early-life stress event. The result of ELSA measurement shows that the elevated serotonin (5-HT) level in the distal colon of NMS rats returned to normal level after treatment with S. chinensis. Moreover, the increase in pain threshold in rats treated with S. chinensis was associated with a decline of the mRNA level of 5-HT(3) receptor in the distal colon. All available results demonstrate that S. chinensis can reverse visceral hypersensitivity induced by neonatal-maternal separation, and the effect may be mediated through colonic 5-HT pathway in the rat.
Phytomedicine: international journal of phytotherapy and phytopharmacology 03/2012; 19(5):402-8. · 2.17 Impact Factor
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Penelope M Y Or,
Francis F Y Lam,
Y W Kwan,
C H Cho,
C P Lau,
H Yu,
G Lin,
Clara B S Lau,
K P Fung,
P C Leung, John H K Yeung
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ABSTRACT: The present study investigated the effects of Radix Astragali (RA) and Radix Rehmanniae (RR), the major components of an anti-diabetic foot ulcer herbal formula (NF3), on the metabolism of model probe substrates of human CYP isoforms, CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, which are important in the metabolism of a variety of xenobiotics. The effects of RA or RR on human CYP1A2 (phenacetin O-deethylase), CYP2C9 (tolbutamide 4-hydroxylase), CYP2D6 (dextromethorphan O-demethylase), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A4 (testosterone 6β-hydroxylase) activities were investigated using pooled human liver microsomes. NF3 competitively inhibited activities of CYP2C9 (IC(50)=0.98mg/ml) and CYP3A4 (IC(50)=0.76mg/ml), with K(i) of 0.67 and 1.0mg/ml, respectively. With specific human CYP2C9 and CYP3A4 isoforms, NF3 competitively inhibited activities of CYP2C9 (IC(50)=0.86mg/ml) and CYP3A4 (IC(50)=0.88mg/ml), with K(i) of 0.57 and 1.6mg/ml, respectively. Studies on RA or RR individually showed that RR was more important in the metabolic interaction with the model CYP probe substrates. RR dose-dependently inhibited the testosterone 6β-hydroxylation (K(i)=0.33mg/ml) while RA showed only minimal metabolic interaction potential with the model CYP probe substrates studied. This study showed that RR and the NF3 formula are metabolized mainly by CYP2C9 and/or CYP3A4, but weakly by CYP1A2, CYP2D6 and CYP2E1. The relatively high K(i) values of NF3 (for CYP2C9 and CYP3A4 metabolism) and RR (for CYP3A4 metabolism) would suggest a low potential for NF3 to cause herb-drug interaction involving these CYP isoforms.
Phytomedicine: international journal of phytotherapy and phytopharmacology 01/2012; 19(6):535-44. · 2.17 Impact Factor
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ABSTRACT: This study investigated the effects of Danshen and its active ingredients on the protein expression and enzymatic activity of CYP1A2 in primary rat hepatocytes. The ethanolic extract of Danshen roots (containing mainly tanshinones) inhibited CYP1A2-catalyzed phenacetin O-deethylation (IC(50)=24.6 μg/ml) in primary rat hepatocytes while the water extract containing mainly salvianolic acid B and danshenshu had no effect. Individual tanshinones such as cryptotanshinone, dihydrotanshinone, tanshinone IIA inhibited the CYP1A2-mediated metabolism with IC(50) values at 12.9, 17.4 and 31.9 μM, respectively. After 4-day treatment of the rat hepatocytes, the ethanolic extract of Danshen and tanshinone I increased rat CYP1A2 activity by 6.8- and 5.2-fold, respectively, with a concomitant up-regulation of CYP1A2 protein level by 13.5- and 6.5-fold, respectively. CYP1A2 induction correlated with the up-regulation of mRNA level of aryl hydrocarbon receptor (AhR), which suggested a positive feedback mechanism of tanshinone I-mediated CYP1A2 induction. A formulated Danshen pill (containing mainly danshensu and salvianolic acid B and the tanshinones) up-regulated CYP1A2 protein expression and enzyme activity, but danshensu and salvianolic acid B, when used individually, did not affect CYP1A2 activity. This study was the first report on the Janus action of the tanshinones on rat CYP1A2 activity.
Phytomedicine: international journal of phytotherapy and phytopharmacology 09/2011; 19(2):169-76. · 2.17 Impact Factor
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ABSTRACT: In this study, the herbal extracts of Schisandra chinensis were demonstrated to inhibit the contractions induced by acetylcholine (ACh) and serotonin (5-HT) in guinea pig ileum, and the 95% ethanol extract was more effective than the aqueous extract. Analysis with High Performance Liquid Chromatography (HPLC) indicated that schisandrin, schisandrol B, schisandrin A and schisandrin B were the major lignans of Schisandra chinensis, and the ethanol extract contained higher amount of these lignans than the aqueous extract. All four lignans inhibited the contractile responses to ACh, with EC(20) values ranging from 2.2±0.4μM (schisandrin A) to 13.2±4.7μM (schisandrin). The effectiveness of these compounds in relaxing the 5-HT-induced contraction was observed with a similar magnitude. Receptor binding assay indicated that Schisandra lignans did not show significant antagonistic effect on muscarinic M3 receptor. In Ca(2+)-free preparations primed with ACh or KCl, schisandrin A (50μM) attenuated the contractile responses to cumulative addition of CaCl(2) by 37%. In addition, schisandrin A also concentration-dependently inhibited ACh-induced contractions in Ca(2+)-free buffer. This study demonstrates that Schisandra chinensis exhibited relaxant effects on agonist-induced contraction in guinea pig ileum, with schisandrin, schisandrol B, schisandrin A and schisandrin B being the major active ingredients. The antispasmodic action of schisandrin A involved inhibitions on both Ca(2+) influx through L-type Ca(2+) channels and intracellular Ca(2+) mobilization, rather than specific antagonism of cholinergic muscarinic receptors.
Phytomedicine: international journal of phytotherapy and phytopharmacology 07/2011; 18(13):1153-60. · 2.17 Impact Factor
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ABSTRACT: Polysaccharide peptide (PSP), isolated from COV-1 strain of Coriolus versicolor, is commonly used as an adjunct in cancer chemotherapy in China. Previous studies have shown that PSP decreased antipyrine clearance and inhibited CYP2C11-mediated tolbutamide 4-hydroxylation in the rat both in vitro and in vivo. In this study, the effects of water extractable fraction of PSP on tolbutamide 4-hydroxylation was investigated in pooled human liver microsomes and in specific human CYP2C9 isoform. PSP (2.5-20μM) dose-dependently decreased the biotransformation of tolbutamide to 4-hydroxy-tolbutamide. Enzyme kinetics studies showed inhibition of tolbutamide 4-hydroxylase activity was competitive and concentration-dependent. In pooled human liver microsomes, PSP had a K(i) value of 14.2μM compared to sulfaphenazole, a human CYP2C9 inhibitor, showed a K(i) value of 0.32μM. In human CYP2C9 isoform, the K(i) value of PSP was 29.5μM and the K(i) value of sulfaphenazole was 0.04μM. This study demonstrated that PSP can competitively inhibit tolbutamide 4-hydroxylation in both pooled human liver microsomes and specific human CYP2C9 in vitro. This study compliments previous findings in the rat that PSP can inhibit human tolbutamide 4-hydroxylase, but the relatively high K(i) values in human CYP2C9 would suggest a low potential for PSP to cause herb-drug interaction.
Phytomedicine: international journal of phytotherapy and phytopharmacology 07/2011; 18(13):1170-5. · 2.17 Impact Factor
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ABSTRACT: This study examined the effect of schisandrin, one of the major lignans isolated from Schisandra chinensis, on spontaneous contraction in rat colon and its possible mechanisms. Schisandrin produced a concentration-dependent inhibition (EC₅₀=1.66 μM) on the colonic spontaneous contraction. The relaxant effect of schisandrin could be abolished by the neuronal Na+ channel blocker tetrodotoxin (1 μM) but not affected by propranolol (1 μM), phentolamine (1 μM), atropine (1 μM) or nicotine desensitization, suggesting possible involvement of non-adrenergic non-cholinergic (NANC) transmitters released from enteric nerves. N(ω)-nitro-l-arginine methyl ester (100-300 μM), a nitric oxide synthase inhibitor, attenuated the schisandrin response. The role of nitric oxide (NO) was confirmed by an increase in colonic NO production after schisandrin incubation, and the inhibition on the schisandrin responses by soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-α]-quinoxalin-1-one (1-30 μM). Non-nitrergic NANC components may also be involved in the action of schisandrin, as suggested by the significant inhibition of apamin on the schisandrin-induced responses. Pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt hydrate (100 μM), a selective P2 purinoceptor antagonist, markedly attenuated the responses to schisandrin. In contrast, neither 8-cyclopentyl-1,3-dipropylxanthine, an antagonist for adenosine A₁ receptors, nor chymotrypsin, a serine endopeptidase, affected the responses. All available results have demonstrated that schisandrin produced NANC relaxation on the rat colon, with the involvement of NO and acting via cGMP-dependent pathways. ATP, but not adenosine and VIP, likely plays a role in the non-nitrergic, apamin-sensitive component of the response.
Phytomedicine: international journal of phytotherapy and phytopharmacology 04/2011; 18(11):998-1005. · 2.17 Impact Factor
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ABSTRACT: Salvia miltiorrhiza (Danshen) is a famous Traditional Chinese medicine used widely in the treatment of cardiovascular and cerebrovascular diseases. This study explored the effects of Danshen capsules commonly used in clinical practice on the liver CYP3A activity in humans and rats. The effects of Danshen extract on liver CYP3A activity were determined by metabolism of model substrates in vitro in human and rat liver microsomes and in the rat in vivo. HPLC was used to determine model substrates and metabolites. Danshen extract (50-2000 µg/mL) competitively inhibited human and rat liver microsomal CYP3A activity with inhibition constant (K(i) ) values of 51 and 65 µg/mL, respectively. In the rat, 14-day Danshen extract treatment (100 mg/kg/day, i.p. or 200 mg/kg/day, p.o.) decreased midazolam clearance (11-14%), with a concomitant increase in area under the curve (AUC; 12-17%) and a decrease in the volume of distribution (11-15%). These studies demonstrated that Danshen extract affected the metabolism of CYP3A substrates through competitive inhibition in human and rat liver in vitro and had no enzyme inducing effects on rat CYP3A in vivo after chronic administration.
Phytotherapy Research 03/2011; 25(11):1653-9. · 2.09 Impact Factor
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ABSTRACT: This study investigated the effect of tanshinones on rat liver microsomal CYP3A2 and 2C11 activity and explored the structure-activity relationship of tanshinones with CYP3A activity. Cryptotanshinone, tanshinone I and tanshinone IIA were competitive CYP3A2 inhibitors (K(i) = 199-243 μM) and CYP2C11 inhibitors (K(i) = 91-118 μM). Dihydrotanshinone was not only a noncompetitive inhibitor of CYP3A2 (K(i) = 110 μM), but also a competitive CYP2C11 inhibitor (K(i) = 55 μM). The structural difference between dihydrotanshinone and tanshinone I at C-15 position of furan ring resulted in the different modes of inhibition on CYP3A activity.
Fitoterapia 01/2011; 82(4):539-45. · 1.85 Impact Factor
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ABSTRACT: This study investigated the effect of Danshen on the pharmacodynamic-pharmacokinetic (PD-PK) effects of midazolam, a model CYP3A probe substrate. The effects of acute and 3-day Danshen treatment on the pharmacokinetics of a low dose midazolam (10 mg/kg, i.p.) were determined in vivo in the rat. Danshen (200 mg/kg, i.p.) treatment decreased midazolam clearance by 16%, with increases in the AUC by 22% and the half-life by 14%. 3-Day Danshen treatment (200 mg/kg/day, i.p.) for 3 days decreased the clearance, with increases in the T(1/2) and AUC. The effects of acute and 3-day Danshen on midazolam-induced hypnosis, serum 1'-hydroxy-midazolam to midazolam ratio and hepatic CYP3A protein expression were determined in the rat. Danshen treatments (100-200 mg/kg, i.p. and 200-500 mg/kg, p.o.) increased the sleeping time (p<0.001) produced by a hypnotic dose of midazolam (50 mg/kg, i.p.) without affecting the sleep latency. Serum 1'-hydroxy-midazolam to midazolam ratio after the hypnotic dose of midazolam was decreased after intraperitoneal Danshen treatment (200 mg/kg) but not after oral treatment at up to 500 mg/kg. All the treatment groups with Danshen, after intraperitoneal and oral administration, decreased hepatic CYP3A protein expression (p<0.05) by about 25%. The results confirmed that Danshen had no enzyme inducing effects on rat CYP3A.
Phytomedicine: international journal of phytotherapy and phytopharmacology 09/2010; 17(11):876-83. · 2.17 Impact Factor
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ABSTRACT: This study investigated the effects of tanshinones on human CYP1A2 (phenacetin O-deethylase), CYP2C9 (tolbutamide 4-hydroxylase), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A4 (testosterone 6beta-hydroxylase) activities in vitro using pooled human liver microsomes and specific human CYP isoforms. Tanshinone I, tanshinone IIA, and cryptotanshinone were potent competitive CYP1A2 inhibitors (K(i)=1.5-2.5 microM); medium competitive inhibitors of CYP2C9 (K(i)=22-62 microM); medium competitive inhibitors of CYP2E1 (K(i)=3.67 microM) for tanshinone I and 10.8 microM for crytotanshinone; but weak competitive inhibitors of CYP3A4 (K(i)=86-220 microM). Dihydrotanshinone was a competitive inhibitor of human CYP1A2 (K(i)=0.53 microM) and CYP2C9 (K(i)=1.92 microM), a noncompetitive inhibitor of CYP3A4 (K(i)=2.11 microM) but an uncompetitive CYP2E1 inhibitor. In conclusion, these results showed that tanshinones inhibited the metabolism of various CYP probe substrates in human liver microsomes and specific human CYP isoforms in vitro. Given that CYP1A2, 2C9, 2E1 and 3A4 are responsible for the metabolism and disposition of a large number of drugs currently used, the potential herb-drug interactions of Danshen preparations containing the major tanshinones with drugs which are substrates of these CYPs may be important.
Phytomedicine: international journal of phytotherapy and phytopharmacology 09/2010; 17(11):868-75. · 2.17 Impact Factor
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ABSTRACT: The effects of the aqueous extract of Salvia miltiorrhiza Bunge (Danshen) on metabolism/pharmacokinetics of caffeine and on liver microsomal CYP1A2 activity in humans and rats have been investigated.
The effects of Danshen aqueous extract on CYP1A2 activity were determined by metabolism of model substrates in the rat in vivo and in humans and rats in vitro. HPLC was used to determine model substrates and metabolites.
In the rat, single dose Danshen aqueous extract treatment (100 or 200 mg/kg, i.p.) decreased metabolism of caffeine to paraxanthine, with overall decrease in caffeine clearance (6-20%), increase in area under the curve (AUC; 7-24%) and plasma half-life (t(1/2) 14-16%). Fourteen-day Danshen aqueous extract treatment (100 mg/kg/day, i.p. or 200 mg/kg/day, p.o.) decreased caffeine clearance (16-26%), increased AUC (18-31%) and prolonged plasma t(1/2) (8-10%). Aqueous extract of Danshen (125-2000 microg/ml) competitively inhibited human and rat liver microsomal CYP1A2 activity with inhibition constant (K(i)) values at 190 and 360 microg/ml, respectively.
These studies demonstrated that Danshen aqueous extract affected the metabolism of CYP1A2 substrates through competitive inhibition and altered their clearance.
The Journal of pharmacy and pharmacology. 08/2010; 62(8):1077-83.
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ABSTRACT: P-Glycoprotein (Pgp) overexpression and alterations in p53 oncogene expression are known to affect chemotherapeutic efficacy in the treatment of human hepatocellular carcinoma (HCC). The present study has demonstrated the anti-HCC potential of cryptotanshinone (1), dihydrotanshinone (2), tanshinone I (3), and tanshinone IIA (4), the active lipophilic constituents of Salvia miltiorrhiza, using MTT and caspase-3 activity assays and poly(ADP-ribose) polymerase cleavage in HepG2, Hep3B, and PLC/PRF/5 cells. THLE-3, a normal human immortalized liver cell line, was used to demonstrate the selective growth inhibitory effect of 3 for a HCC cell line. Compound 1 suppressed doxorubicin efflux, a process mediated by P-glycoprotein, in a Pgp-overexpressed HepG2 subclone (R-HepG2 cells). Despite its moderate cytostatic and pro-apoptotic effects and minimal influence on doxorubicin efflux, 4 provided the best synergism with doxorubicin as determined by the Combination Index, the Loewe additivity model, and the Bliss independence criterion.
Journal of Natural Products 05/2010; 73(5):854-9. · 3.13 Impact Factor
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ABSTRACT: Danshen (Salvia miltiorrhiza) is commonly used in the treatment of cardiovascular and cerebrovascular diseases. In this study, the effects of a Danshen ethyl acetate extract containing the major tanshinones, an aqueous extract containing salvianolic acid B and danshensu, and individual tanshinones (tanshinone I, tanshinone IIA and cryptotanshinone) on warfarin hydroxylation was investigated. In rat liver microsomes study, the ethyl acetate extract of Danshen, tanshinone I, tanshinone IIA and cryptotanshinone decreased the formation of 4'-, 6- and 7-hydroxy-warfarin, mediated by CYP1A1, CYP2C6 and CYP2C11 activities, respectively. The aqueous extract of Danshen had no effect on warfarin hydroxylation. Both acute and 3-day Danshen treatment significantly decreased Cmax and prolonged Tmax of warfarin in the rats. The formation of 4'- and 7-hydroxywarfarin in vivo was decreased significantly after 3-day danshen treatment. In steady state study in vivo, the steady state plasma warfarin concentration was increased by 23% when Danshen was co-administered. The results suggest that tanshinones inhibited CYP1A1, CYP2C6 and CYP2C11-mediated warfarin metabolism both in vitro and in vivo in the rats. The timing of Danshen intake relative to warfarin contributed to different pharmacokinetics of the free warfarin concentration.
Phytomedicine: international journal of phytotherapy and phytopharmacology 08/2009; 17(3-4):219-26. · 2.17 Impact Factor
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ABSTRACT: The role of reactive oxygen species (ROS) and p38 mitogen-activated protein kinases (MAPK) in tanshinones-induced apoptosis was investigated in HepG2 cells in this study. The major tanshinones (cryptotanshinone, dihydrotanshinone, tanshinone I, tanshinone IIA), isolated from Salvia miltiorrhiza, inhibit cell growth and induce caspase-dependent apoptosis concentration-dependently, with dihydrotanshinone being the most potent. All four tanshinones were found to induce ROS generation, but only dihydrotanshinone can induce activation of p38 MAPK. The p38 MAPK activation by dihydrotanshinone was inhibited by N-acetyl cysteine pretreatment. It is thus concluded that ROS-mediated p38 MAPK activation plays a vital role in dihydrotanshinone-induced apoptosis in HepG2 cells.
Cancer letters 06/2009; 285(1):46-57. · 4.86 Impact Factor
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ABSTRACT: In this study, six major xanthones, isolated and identified from Halenia elliptica were investigated for their vasodilatory actions in isolated rat coronary artery. The xanthones, including 1-hydroxy-2,3,5-trimethoxy-xanthone (HM-1), 1-hydroxy-2,3,4,7-tetramethoxy-xanthone (HM-2), 1-hydroxy-2,3,4,5-tetramethoxy-xanthone (HM-3), 1,7-dihydroxy-2,3,4,5-tetramethoxy-xanthone (HM-4), 1,5-dihydroxy-2,3-dimethoxy-xanthone (HM-5) and 1,7-dihydroxy-2,3-dimethoxy-xanthone (HM-7) caused vasodilation in the coronary artery pre-contracted with 1 microM 5-hydroxytryptamine (5-HT), with EC(50) values ranging from 1.4+/-0.1 microM (HM-1) to 6.6+/-1.4 microM (HM-2). The EC(50) values of the other xanthones were between those of HM-1 and HM-2. Removal of endothelium of the coronary artery led to decreases in the vasorelaxant effects of HM-1, HM-7 but not HM-2, HM-3, HM-4 and HM-5. Our results showed that xanthones isolated from Halenia elliptica are vasoactive substances which exhibit either endothelium-dependent or endothelium-independent mechanisms in rat coronary artery. The potency and mechanism(s) of the vasorelaxant effects of these xanthones may be relevant to the structure-activity differences in the level and the position of the substituent groups with the primary xanthone structure.
Phytomedicine: international journal of phytotherapy and phytopharmacology 05/2009; 16(12):1144-50. · 2.17 Impact Factor
