Polysaccharide peptides from Coriolus versicolor competitively inhibit model cytochrome P450 enzyme probe substrates metabolism in human liver microsomes.
Polysaccharide peptide (PSP)
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 (1.25-20 p.M) dose-dependently decreased CYP1A2-mediated metabolism of phenacetin to paracetamol ([IC.sub.50] 19.7 [micro]M) and CYP3A4-mediated metabolism of testosterone to 6[beta]-hydroxytestosterone ([IC.sub.20] 7.06 [micro]M). Enzyme kinetics studies showed the inhibition of CYP1A2 activity was competitive and concentration-dependent ([K.sub.i]=18.4 [micro]M). Inhibition of testosterone to 6[beta]-hydroxytestosterone was also competitive and concentration-dependent ([K.sub.i]= 31.8 [micro]M). Metabolism of dextromethorphan to dextrorphan (CYP2D6-mediated) and chlorzoxazone to 6-hydroxychlorzoxazone (CYP2E1-mediated) was only minimally inhibited by PSP, with [IC.sub.20] values at 15.6 [micro]M and 11.9 [micro]M, respectively. This study demonstrated that PSP competitively inhibited the CYP1A2-and CYP3A4mediated metabolism of model probe substrates in human liver microsomes in vitro. The relatively high [K.sub.i] values for CYP1A2 and CYP3A4 would suggest a low potential for PSP to cause herb-drug interaction related to these CYP isoforms.
[c] 2011 Elsevier GmbH. All rights reserved.
Coriolus versicolor is found worldwide and its biological activity varies with the strain and the habitat in which it grows (Monro 2003; Jeong et al. 2006; Tao et al. 2009; Cui et al. 2010). Polysaccharide peptide (PSP), a protein-bound polysaccharide isolated from the Chinese fungus (Yun Chi; Coriolus versicolor strain COV-1), has shown immunomodulatory effect in a number of human tumour cell lines (Wang et al. 1999; Yang and Zhang 2009), human peripheral blood mononuclear cells (Li et al. 2010) and in animals (Yang et al. 1993; Li et al. 2008). Like other mushroom glucans and proteoglycans, PSP has been suggested to be useful as an adjunct to chemotherapy and radiotherapy (Kidd 2000). Phase three clinical trials completed at 14 hospitals throughout China since 1997 suggested that PSP improved the quality of life of the patients by decreasing treatment-related symptoms such as fatigue, loss of appetite, nausea and vomiting, and pain in patients (Liu et al. 1999; Zhang et al. 1999). Polysaccharide Krestin (PSK), a similar compound to PSP, was isolated from CM-101 strain of Coriolus versicolor significantly extended the 5-year survival rates of patients with different types of cancer in Japan (Go and Chung 1989; Mitomi et al. 1992; Hayakawa et al. 1993; Ogoshi et al. 1995). PSK, PSP and similar products containing polysaccharide peptides are now commonly used as health supplements in the Southeast Asia regions.
The popular use of PSP as an adjuvant to cancer treatment was, however, not matched by the information known on its bioactivity and metabolism. Most of the metabolic studies of PSP and PSK (Krestin) have been performed using in vitro models. It has been predicted that PSP may be metabolised to polysaccharides and smaller peptides in vivo. An early study showed that PSP decreased the covalent binding of paracetamol to microsomal proteins, suggesting that generation of the P450-mediated chemically reactive metabolite of paracetamol was decreased by PSP (Yeung et al. 1994). Further studies showed that the phase II conjugates of paracetamol were significantly increased by PSP in the rat, which may reflect either phase II enzyme induction or a decrease in the extent and rate of metabolism which utilized the phase I pathways (Yeung et al. 1995). Other studies also showed the effects of PSP on cyclophosphamide clearance, possibly through metabolic mechanisms involving cytochrome P450 in the rat (Chan and Yeung 2006a). The metabolism of cyclophosphamide is through P450-mediated oxidative pathways involving CYP2B6, CYP2C9 and CYP3A4 (Chang et al. 1993). As a pro-drug, cyclophosphamide requires activation by CYP-mediated 4-hydroxylation to form the active cytotoxic nitrogen mustards (Zhang et al. 2005). PSP treatment for three days decreased the clearance (30-35%) and increased the plasma half-life (55%) of antipyrine (Chan and Yeung 2006b). As antipyrine and cyclophosphamide are metabolised by different CYP isoforms, the involvement of individual CYP isoforms could not be established. More recent studies have shown that PSP inhibited rat CYP2C11-mediated tolbutamide 4-hydroxylation in vitro and in vivo (Yeung et al. 2006). In human liver microsomes and specific human CYP2C9 isoforms, PSP acted as a competitive inhibitor on the metabolism of tolbutamide (Yeung and Or 2011). The aim of this study was to investigate the effects of PSP on the other important CYP isoforms (CYPs 1A2, 2D6, 2E1 and 3A4) which are responsible for the metabolism of a large variety of drugs in man. The effect of PSP on the human CYP isoforms was investigated to determine the potential of PSP in affecting CYP medicated phase I metabolism in man, using phenacetin (CYP1A2), dextrophan (CYP2D6), chlorzoxazone (CYP2E1) and testosterone (CYP3A4) as the respective model probe substrates.
Materials and methods
Chemicals and reagents
Polysaccharide peptide (PSP), isolated from deep-layer cultivated mycelia of Coriolus versicolor, was provided by Winsor Health Products Ltd. (Hong Kong). Pooled human liver microsomes (HLMs) were obtained from GenTest Corporation (Woburn, MA, USA) and stored at - 80 [degrees]C until use. Phenacetin, paracetamol, metacetamol, furafylline, testosterone, 6[beta]-hydroxytestosterone, corticosterone, ketoconazole, chlorpropamicle, chlorpheniramine, dextrorphan, dextromethorphan, chlorzoxazone, 6-hydroxychlorzoxazone, sodium diethyl-dithiocarbamate, n-glucose 6-phosphate (G6P), glucose 6-phosphate dehydrogenase (G6PDH), [beta]-nicotinamide adenine dinucleotide phosphate (NADP), and Tris-HC1 were pur-chased from Sigma Chemical Co. (St. Louis, MO, USA). Acetonitrile (HPLC grade) was purchased from Labscan Analytical Sciences (Bangkok, Thailand). Methanol (HPLC grade) was purchased from BDH Laboratory Supplies (Poole, UK), ethyl acetate (HPLC grade) from Fisher Chemicals (Leicester, UK). Acetic acid, glacial, (HPLC grade) was from Scharlau Chemie (Barcelona, Spain). Carbon monoxide was supplied by Hong Kong Special Gas Co.
Properties of PSP water extract
The PSP sample was supplied and authenticated by Professor Q.Y. Yang (Shanghai Teachers' University, China) with initial screening test carried out to ensure the PSP was free from endotoxins and contaminants such as lipopolysaccharide (LPS). The PSP sample has molecular weight of 100 kDaltons, as analysed by gel electrophoresis (Zhou and Yang 1999) The water soluble fraction of PSP was obtained by boiling the whole PSP extract powder in distilled water, with the insoluble material removed by centrifugation and filtration of the supernatant using a 0.22-[micro]m filter. Spectral analysis (wavelength 200-400 nm) did not show obvious changes between the whole PSP extract and the water extract, except for a slightly lower absorbance at 275 nm for the latter (Yeung and Or 2011). The same batch of PSP, composed of 90% polysaccharides and 10% peptides, has been used in this and the previous studies for consistency and comparison, with the same composition of the sugars and amino acids in the peptide and polysaccharide peptide (Tables la and 1 b).
Effect of PSP water extract on human phenacetin 0-deethylase (CYP1A2) activity in vitro
CYP1A2 activity was assessed by formation of paracetamol from phenacetin by the method reported previously, with modifications (Kobayashi et al. 1998; Wang et al. 2010). The incubation mixture (final volume of 500 [micro]l in 0.05 M Tris/KC1 buffer, pH 7.4) consisted of an NADPH-regenerating system (1.3 mM NADP, 3.3 mM G6P, 0.4 units/ml G6PDH, and 3.3 mM [MgCl.sub.2]) and 0.8 mg/ml pooled human liver microsomes. For inhibition study. 50 [micro]M phenacetin was used. For kinetic studies, phenacetin concentrations ranged from 12.5 to 100 [micro]M. The final concentrations of PSP were 1.25-20 [micro]M. Furafylline, a selective CYP1A2 inhibitor, was used as positive control. HPLC analyses of phenacetin, paracetamol and metacetamol (internal standard) were performed on a Hewlett-Packard 1050 Series instrument with UV detection at 245 nm.
Effect of PSP water extract on human debrisoquine 4-hydroxylase (CYP2D6) activity in vitro
CYP2D6 activity was assessed by the formation of dextrorphan from the CYP2D6 probe dextromethorphan. The incubation mixture (final volume 500[micro]l, in 0.05 M Tris/KCI buffer, pH 7.4) consisted of an NADPH-regenerating system (1.3 mM NADP, 3.3 mM G6P, 0.4 units/mI G6PDH, and 3.3 mM [MgCl.sub.2]), 100 [micro]M dextromethorphan and 0.8 mg/m1 pooled human liver microsomes. PSP was present at 1.25-20 [micro]M. The reaction was initiated by adding protein to incubation mixture and incubated for 20 min at 37 [degrees]C. Incubations were terminated by adding 500 [micro]l of ice-cold acetonitrile, centrifuged and the supernatant extracted with 500 [micro]l ethyl acetate. The organic layer was dried under a gentle stream of nitrogen, resuspended in methanol, and used for HPLC analysis.
Dextrorphan, dextromethorphan and chlorpheniramine (internal standard) were separated on Agilent ZORBAX Eclipse XDB-C8, 5[micro]M (150 mm x 4.6 mm) with Eclipse XDB-C8 guard column. The mobile phase consisted of 30% acetonitrile in 0.1% triethylamine with perchloric acid at pH 3.0, using a flow rate of 0.5 ml/min in isocratic mode. Detection was by UV absorbance at 220 nm.
Effect of PSP water extract on human chlorzoxazone 6-hydroxylase (CYP2E1) activity in vitro
CYP2E1 activity was assessed by formation of 6-hydroxy chlorzoxazone from chlorzoxazone by the method reported previously (Wang et al. 2010). Human liver microsomal protein (0.8 mg) was incubated in incubation buffer (0.05 M phosphate buffer with 3.3 mM [MgCl.sub.2]) containing 1 mM NADPH, and chlorzoxazone (25-200 [micro]M) in a total volume of 200 [micro]l. The incubation mixture was pre-incubated for 5 min at 37 [degrees]C before adding NADPH. Phenacetin (10 [micro]l of 50 [micro]g/m1) was used as internal standard. The 1-h incubation was initiated by NADPH at 37 [degrees] C thermomixer, at 800 rpm. The reaction was terminated by adding 200 [micro]l ice-cold acetonitrile, centrifuged and the supernatant was extracted with 400 [micro]l of ethyl acetate and the organic layer dried under a gentle stream of nitrogen. The residue was reconstituted with a ACN/[H.sub.3][PO.sub.4] mixture (500 [micro]l ACN with 1.2 ml [H.sub.3][PO.sub.4]) for HPLC analysis (Wang et al. 2010). For inhibition kinetic studies, PSP (2.5-20 [micro]M) were used, with the substrate chlorzoxazone (2.5-200 [micro]M). Sodium diethyl-dithiocarbamate (25-200 [micro]M) was used as positive control for CYP2E1 inhibition.
Effect of PSP water extract on human testosterone 613-hydroxylase (CYP3A4) activity in vitro
CYP3A4 activity was assessed by formation of 6[beta]-hydroxytestosterone from testosterone by the methods previously reported (Purdon and Lehman-McKeeman 1997; Wang et al. 2010; Wang and Yeung 2011). Briefly, a final volume of 500 Ed of 100 mM phosphate-buffered incubation medium (pH 7.4) contained 3.3 mM [MgCl.sub.2], 1.3 mM [beta]-NADP, 3.3 mM G6P, 0.4 units/m1 G6PDH and 0.5 mg/ml microsomal protein and various concentrations of PSP. For inhibition study, testosterone (50 [micro]M) was used. For enzyme kinetic studies, testosterone concentrations used were from 25 to 200 [micro]M. The final concentrations of PSP used were 1.25-20 [micro]M. Ketoconazole (0.025-0.50 [micro]M) was used as positive control. The reaction was initiated by adding protein to incubation mixture and incubated for 20 min at 37 [degrees]C. Incubations were terminated by adding 500 [micro]l of ice-cold acetonitrile, centrifuged and the supernatant extracted with 500 [micro]l ethyl acetate which was dried under a gentle stream of nitrogen, resuspended in methanol (120 [micro]l) and used for HPLC analysis (Wang et al. 2010)
Inhibition kinetics studies
Inhibition kinetics studies were performed for CYP1A2 and CYP3A4 probe substrates only, since PSP only marginally inhibited the metabolism of model CYP2D6 ([IC.sub.20] = 15.6 [micro]M) and model CYP2E1 ([IC.sub.20] = 11.8 [micro]M) substrates. PSP (2.5-20 [micro]M) and phenacetin (12.5-100 [micro]M) or testosterone (25-200 [micro]M) were used for inhibition kinetics studies, using a protocol routinely used for investigating herb-drug interaction potential for natural products (Wang et al. 2010). Furafylline, a selective CYP1A2 inhibitor, was used as a positive control for phenacetin 0-deethylase inhibition (0.1-0.8 [micro]M). Ketoconazole, a selective CYP3A4 inhibitor, was used as a positive control for testosterone 6b-hydroxylase inhibition (0.1-0.8 [micro]M).
Statistical analysis of the data was carried out using ANOVA by a computer program (Statview 9.0, Abacus Concepts, USA). Enzyme kinetics data were fitted by non-linear regression analysis using GraphPad Prism 4 (GraphPad Software, CA, USA). [IC.sub.20] values (concentration of inhibitor to cause 20% inhibition of original enzyme activity) or [IC.sub.50] values (concentration of inhibitor to cause 50% inhibition of original enzyme activity) were determined by GraFit where appropriate using the following equation:
V = [V.sub.o]/(1 + 1[(1/[IC.sub.50]).sup.S])
where [V.sub.o] is uninhibiter velocity, V is observed velocity, S is slope factor and I is inhibitor concentration. A Lineweaver-Burk plot is a double reciprocal plot in which varying substrate concentrations are plotted against reaction velocities to obtain linear transformation. The enzyme parameter Michaelis constant ([K.sub.m]) and [V.sub.max] values were obtained from Lineweaver-Burk plot. The inhibition constant ([K.sub.i), the inhibitor concentration at which the reaction is half of the maximal rate, was obtained by a secondary plot using the slope of the primary Lineweaver-Burk plot and fit by GraphPad Prism 4.
Inhibition of metabolism of model CYP1A2, 2D6, 2E1 and 3A4 probe substrates by PSP in pooled human liver microsomes
To investigate if PSP affect the catalytic activity of P450 isoforms, the probe reaction assays were conducted with various concentrations of PSP. Specific inhibitors of CYP1A2, 2D6, 2E1 and 3A4 isoforms were used as positive controls. PSP inhibited CYP1A2 activity in human liver microsomes, with [IC.sub.50] value of 19.7 [micro]M (Fig. 1). Inhibition curves of PSP against the other CYP model probe substrates studied were not as steep as the CYP1A2 substrate, with [IC.sub.20] values of 15.6 [micro]M,11.9 [micro]M and 7.06 [micro]M for the model CYP2D6, CYP2E1 and CYP3A4 probe substrates, respectively (Figs. 2-4). The inhibition parameters, including [IC.sub.20], [IC.sub.50] and [K.sub.i] values were summarized in . PSP only slightly inhibited the metabolism of CYP2D6 and CYP2E1 substrates, with the [IC.sub.50] values beyond the concentration range studied and suggesting minimal interference with these enzyme activities.
Table 2 Inhibition of model CYPs substrates metabolism by PSP water extract: a summary of inhibition constants. Model probe [IC.sub20] [IC.sub.50] [K.sub.i]([mu]M) substrate (M) (pM) Phenacetin 5.4 19.7 18.4 (CYP1A2) Tolbutamide 3.8 13.2 14.3 (CYP2C9) (a) Dextromethorphan 15.6 - n.d. (CYP2D6) Chlorzoxazone 11.9 - n.d. (CYP2E1) Testosterone 7.6 - 31.8 (CYP3A4) n.d., not determined. (a.) Data from Yeung and Or (2011).
Inhibition kinetic analysis
Enzyme inhibition kinetic studies were performed with CYP1 A2 and 3A4 probe substrates to further characterize the inhibition of these CYP enzymes by PSP. Based on the analysis of non-linear regression of inhibition data and Dixon plots (Figs. 5-6), PSP exhibited competitive inhibition against CYP1A2 activity, with [K.sub.i] value of 18.4 [micro]M for CYP1A2 (Fig. 5a-b). The inhibitory effect of PSP on phenacetin 0-deethylation was less effective than furafylline, a potent and specific human CYP1A2 inhibitor. PSP exhibited competitive inhibition against CYP3A4 activity, with [K.sub.i] value of 31.8 [micro]M (Fig. 6a-b). The inhibitory effect of PSP on testosterone 6[beta]-hydroxylation was less effective than ketoconazole, a potent and specific human CYP3A4 inhibitor.
Natural products are increasingly used in different countries as dietary supplements, natural health products, phytomedicines or traditional medicines (Foster et al. 2005). The potential interaction of these products with drugs represents a major safety concern in patients receiving drug treatment for chronic illness/disease, especially when the drugs concerned have narrow therapeutic indices (Hu et al. 2005). Induction or inhibition of drug metabolising enzymes such as cytochrome P450 (CYP) and/or drug transporters such as P-glycoprotein (P-gp) are among the possible mechanisms for the increase or decrease in the bioavailability of drugs when herbal/botanical products are co-administered (Zhou et al. 2003, 2004). Despite numerous studies have been carried out with PSK and PSP, the metabolism of these polysaccharide peptides in vivo have not been fully illustrated. One of the difficulties may be the lack of suitable analytical methods to quantify the metabolites which are postulated to be polysaccharides and smaller peptides. Thus, most of the drug interaction studies were focused on the ability of PSP to alter the metabolism of model probe substrates in vitro and in vivo. Previous studies with PSP have shown that coadministration of PSP decreased cyclophosphamide clearance in the rat in vivo (Chan and Yeung 2006b), inhibited rat CYP2C11-mediated tolbutamide 4-hydroxylation in the rat (Yeung et al. 2006). More recently, PSP has been shown to inhibit the formation of 4-hydroxy-tobultamide concentration-dependently in pooled human liver microsomes and in specific human CYP2C9 isoform (Yeung and Or 2011).
CYP1A2 enzyme plays an important role in the metabolism of several clinically used drugs including theophylline, clozapine, and tacrine, and foodborne procarcinogens such as polycyclic aromatic hydrocarbons or imidazoquinoline derivatives (Carrillo et al. 2000; Zhou et al. 2003; Faber et al. 2005). Results from the current study showed that PSP competitively inhibited human CYP1A2 activity, as indicated by the change in paracetamol/phenacetin (metabolite/parent drug) ratio. Inhibition kinetics studies showed that PSP exhibited a [K.sub.i] of 18.41 [micro]M on CYP1A2 model substrate, which is similar in magnitude reported for human CYP2C9 model substrate (Yeung and Or 2011). Thus, the potential for PSP to cause significant interaction with CYP1A2 substrates would be relatively low.
The effects of PSP on the metabolism of CYP2D6 and CYP2E1 were minimal, with only [IC.sub.20] values recorded. CYP2D6 is a cytochrome P450 enzyme that catalyzes hydroxylation of many drugs and environmental chemicals, such as debrisoquine, adrenergic receptor antagonists and tricyclic antidepressants (Ingelman-Sundberg and Sim 2010). This enzyme is deficient in up to ten percent of the Caucasian population (De Gregori et al. 2010). CYP2E1 is one of the major cytochrome P450 enzymes that it is involved in a number of low molecular mass xenobiotics metabolism, including ethanol, long chain fatty acids, paracetamol, chlorzoxazone, and anaesthetics such as enflurane, sevoflurane, methoxyflurane and isoflurane. Other drugs such as paracetamol and isoniazid, are among other CYP2E1 substrates with toxicological and clinical significance. The hydrophobic active site of CYP2E1 has been observed as the smallest compared with other CYP enzymes to complement low molecular mass substrates (Porubsky et al. 2008). PSP is however relatively large in size and this may explain the minimal interaction of PSP with CYP2E1.
CYP3A4 is one of the most abundant drug-metabolising P450 isoforms in human liver microsomes which accounts for approximately 40% of the total P450 (Lehmann et at 1998). CYP3A4 enzyme is one of the dominant CYP enzymes in both the liver and extrahepatic tissues which plays an important role in the oxidation of xenobiotics and contribute to the biotransformation of about 60% therapeutic drugs currently in use (Kanazu et al. 2004). Characterization of the CYP3A4 isoform responsible for the metabolism of drugs and herbal constituents is important for the identification of potential drug-drug or herb-drug interactions in humans (Gurley et al. 2002; Zhou et al. 2004). Results from the current study showed that PSP competitively inhibited human CYP3A4 activity, as indicated by the 6-hydroxy-testosterone/testosterone (metabolite/parent drug) ratio. Inhibition kinetics studies showed that PSP exhibited a [K.sub.i] of 31.8 [micro]M on CYP3A4 model substrate, which is larger than that of CYP1A2 and CYP2C9. This finding is in line with a previous in vivo study in which a Coriolus versicolor based-product (I'm Yunity) did not affect the CYP3A4-mediated erythromycin metabolism in nun (Nicandro et al. 2007). A recent study on the bio-activation capacity of paracetamol in human cytochrome P450 showed that CYP3A4, followed by CYP2E1, CYP1A2 and CYP2D6, had the highest capacity at therapeutic and toxic paracetamol concentrations (Laine et al. 2009). This recent report may be relevant to early studies in which PSP decreased the covalent binding of paracetamol to microsomal proteins, suggesting that generation of the P450-mediated chemically reactive metabolite of paracetamol was decreased in the presence of PSP (Yeung et al. 1994). In this study, PSP act as competitive inhibitor for human CYP1A2, CYP3A4 and to a smaller extent CYP2D6 and CYP2E1 which could explain the decrease in the extent and rate of metabolism of paracetamol which utilized the CYP-mediated phase I pathways (Yeung et al. 1995).
In conclusion, experimental data from this and previous studies indicated that PSP can behave as moderate competitive inhibitors for model probe substrates of human CYP1A2, CYP2C9 and CYP3A4 and weak inhibitors for model probe substrates of human CYP2D6 and CYP2E1. The relatively high [K.sub.i] values for CYP1A2 and CYP3A4 would, however, suggest a low potential for PSP to cause significant herb-drug interaction related to these CYP isoforms. Further PD/PM studies, however, would be required the safe use of PSP when coadministered with other drugs in vivo.
The authors gratefully acknowledge the supply of PSP from The Hong Kong Association for Health Care Ltd. and Professor Q.Y. Yang (Shanghai Teachers' University, China) for authentication of the PSP sample.
* Corresponding author. Tel.: +852 3943 6864; fax: +852 2603 5139. E-mail address: email@example.com (J.H.K. Yeung).
0944-7113/$ -see front matter [c]2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2011.09.077
Carrillo, J.A., Christensen, M., Ramos, Si., Alm, C., Dahl, M.L., Benitez, J., Bertilsson L, 2000. Evaluation of caffeine as an in vivo probe for CYP1A2 using measurements in plasma, saliva, and urine. Ther. Drug Monit. 22, 409-417.
Chan, S.L., Yeung, J.H.K., 2006a. Effects of polysaccharide peptide (PSP) from Coriolus versicolor on the pharmacokinetics of cyclophosphamide in the rat and cytotoxicity in HepG2 cells. Food Chem. Toxicol. 44, 689-694.
Chan, S.L., Yeung, J.H.K., 2006b. Modulation of antipyrine clearance by polysaccharide peptide isolated from Coriolus versicolor in the rat. Food Chem. Toxicol. 44, 1607-1612.
Chang, T.K., Weber, G.F., Crespi, C.L., Waxman, D.J., 1993. Differential activation of cyclophosphamide and ifosphamide by cytochrome P450 2B and 3A in human liver microsomes. Cancer Res. 53. 5629-5637.
Cui, J.J., Yuan, J.F., Zhang, Z.Q., 2010. Anti-oxidation activity of the crude polysaccharides isolated from Polygonum Cillinerve (Nakai) Ohwi in immunosuppressed mice. J. Ethnopharmacol. 132, 512-517.
De Gregori, M., Allegri, M., De Gregori, S., Garbin, G., Tinelli, C., Regazzi, M., Govoni, S., Ranzani, G.N., 2010. How and why to screen for CYP2D6 interindividual variability in patients under pharmacological treatments. Curr. Drug Meta. 11, 276-282.
Faber, M.S., Jetter, A., Fuhr, U., 2005. Assessment of CYP1 A2 activity in clinical practice: why, how, and when? Basic Clin. Pharmacol. Toxicol. 97, 125-134.
Foster, B.C., Arnason, J.T., Briggs, C.J., 2005. Natural health products and drug disposition. Annu. Rev. Pharmacol. Toxicol. 45, 203-226.
Go, P., Chung, C.H., 1989. Adjuvant PSK immunotherapy in patients with carcinoma of the nasopharynx. J. Int. Nled. Res. 17, 141-149.
Gurley, B.J., Gardner, S.F., Hubbard, MA., Williams, D.K., Gentry, W.B., Cui. Y., Ang, C.V., 2002. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin. Pharmacol. Ther. 72, 276-287.
Hayakawa, K., Mitsuhashi, N., Saito, V, Takahashi, M., Katano, S., Shiojima, K., Furuta, M., Niibe, H., 1993. Effect of krestin (PSK) as adjuvant treatment on the prognosis after radical radiotherapy in patients with non-small cell lung cancer. Anticancer Res. 13,1815-1820.
Hu, Z., Yang, X., Ho, P.C.L., Chan, S.Y., Heng, P.W.S., Chan, E, Duan, W., Koh, H.L. Zhou, S., 2005. Herb-drug interactions: a literature review. Drugs 65 (9), 1239-1282.
Ingelman-Sundberg, M., Sim, S.C., 2010. Pharmacogenetic biomarkers as tools for improved drug therapy; emphasis on the cytochrome P450 system. Biochem. Biophys. Res. Commun. 396, 90-94.
Jeong, S.C., Yang, B.K., Kim, G.N., Jeong, H., Wilson, M.A., Cho, Y., Rao, K.S., Song, C.H., 2006. Macrophage-stimulating activity of polysaccharides extracted from fruiting bodies of Coriolus versicolor (Turkey tail mushroom). J. Med. Food 9, 175-181.
Kanazu, T., Yamaguchi, Y., Okamura, N., Baba, T., Koike, M., 2004. Model for the drug-drug interaction responsible for CYP3A enzyme inhibition. II: Establishment and evaluation of dexamethasone-pretreated female rats. Xenobiotica 34, 403-413.
Kidd, P.M., 2000. The use of mushroom glucans and proteoglycans in cancer treatment. Altern. Med. Rev. 5, 4-27.
Kobayashi, K., Nakajima, M., Chiba, K., Yamamoto, T., Tani, M., Ishizaki, T., Kuroiwa, Y., 1998. Inhibitory effects of antiarrhythmic drugs on phenacetin 0-deethylation catalysed by human CYP1A2. Br. J. Clin. Pharmacol. 45, 361-368.
Lai ne, J.E., Au riola, S., Pasanen, M.Juvonen, R.O., 2009. Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica 39, 11-21.
Li, J., Bao, Y., Lam, W., Li, W., Lu, F., Zhu, X., Liu, J., Wang, H., 2008. Immunoregulatory and anti-tumor effects of polysaccharopeptide and Astragalus polysaccharides on tumor-bearing mice. Immunopharmacol. lmmunotoxicol. 30, 771-782.
Li, W., Liu, M., Lai, S., Xu, C., Lu, F., Xiao, X., Bao, Y., 2010. Immunomodulatory effects of polysaccharopeptide (PSP) in human PBMC through regulation of TRAF6/TLR immunosignal-transduction pathways. Immunopharmacol. lmmunotoxicol. 32, 576-584.
Liu, J.X., Zhou, J.Y., Liu, T.F., 1999. Phase III clinical trial for the Yun Zhi polysacchride (PSI)) capsules. In: Yang, Q.Y. (Ed.), Advanced Research in PSP 1999. The Hong Kong Association for Health Care Limited, Hong Kong, pp. 295-303.
Lehmann, J.M., McKee, D.D., Watson, M.A., Willson, T.M., Moore, J.T., Kliewer, S.A., 1998. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 102, 1016-1023.
Mitomi, T., Tsuchiya, S., lijima, N., Aso, K., Suzuki, K., Nishiyama, K., Amano, T., Takahashi, T., Murayama, N., Oka, H., et al., 1992. Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. The Cooperative Study Group of Surgical Adjuvant Immunochemotherapy for Cancer of Colon and Rectum (Kanagawa). Dis. Colon. Rectum. 35, 123-130.
Monro, J.A., 2003. Treatment of cancer with mushroom products. Achiv. Environ. Health 58, 533-537.
Nicandro, J.P., Tsourounis, C.. Frassetto, L. Guglielmo, B.J., 2007. in vivo effect of I'm-Yunity on hepatic cytochrome P450 3A4. J. Herb. Pharmacother. 7, 39-56.
Ogoshi, K., Satou, H., Isom, K., Mitomi, T., Endoh, M., Sugita, M., 1995. Possible predictive markers of immunotherapy in esophageal cancer: retrospective analysis of a randomized study. Cancer Invest. 13, 363-369.
Porubsky, P.R., Meneely, K.M., Scott, EE, 2008. Structures of human cytochrome P450 2E1. Insights into the binding of inhibitors and both small molecular weight and fatty acid substrates. J. Biol. Chem. 283, 33698-33707.
Purdon, M.P., Lehman-McKeeman, LD., 1997. Improved high-performance liquid chromatographic procedure for the separation and quantification of hydroxytestosterone metabolites. J. Pharmacol. Toxicol. Methods 37, 67-73.
Tao, Y.Z., Zhang, Y.Y., Zhang, L, 2009. Chemical modification and anti-tumor activities of two polysaccharide-protein complexes from Pleurotus tuber-regium. Int. J. Biol. Macromol. 45, 109-115.
Wang, S.Y., Hu, M.L., Yang, X.T., 1999. Growth inhibition and apoptosis in human leukemia cells induced by cytokines released from PSP-activated blood mononuclear cells. ln: Yang, Q.Y. (Ed.), Advanced Research in PSP 1999. The Hong Kong Association for Health Care Limited, Hong Kong, pp. 128-130.
Wang, X., Yeung, J.H.K., 2011. Effects of Salvia miltiorrhiza extract on the liver CYP3A activity in humans and rats. Phytother. Res., doi:10.1002/ptr.3472; March 21 (Epub ahead of print).
Wang, X., Cheung, C.M., Lee, W.Y.W., Or, P.M.Y., Yeung, J.H.K., 2010. Major tanshinones of Danshen (Salvia miltiorrhiza) exhibit different modes of inhibition on human CYP1A2, CYP2C9, CYP2E1 and CYP3A4 activities in vitro. Phytomedicine 17, 868-875.
Yang, L.Q., Zhang, LM., 2009. Chemical structural and chain conformational characterization of some bioactive polysaccharides isolated from natural resources. Carbohydr. Polym. 76, 349-361.
Yang, Q.Y., Hu, Y.J., Li, X.Y., Yang, J.C., Liu, J.X., Liu, T.F., Xu, G.M., Liao, M.L., 1993. A new biological response modifier substance-PSP. In: Yang, Q.Y., Kwok, C.Y. (Eds.), 1993 PSP International Symposium, Anthology of Theses and Abstracts. Fudan University Press, Shanghai, pp. 55-72.
Yeung, J.H.K., Chiu, L.C.M., Ooi, V.E., 1994. Effect of polysaccharide peptide (PSP) on glutathione and protection against paracetamol-induced hepatotoxicity in the rat. Methods Find. Exp. Clin. Pharmacol. 19, 723-729.
Yeung, J.H,K., Chiu, LC.M., Ooi, V.E., 1995. Effect of polysaccharide peptide (PSP) on in vivo sulphation and glucuronidation of paracetamol in the rat. Eur. J. Drug Metab. Pharmacokinet. 20, 287-292.
Yeung, J.H.K., Chan, S.L., Or, P.M.Y., 2006. Polysaccharide peptides from COV-1 strain of Coriolus versicolor inhibit tolbutamide 4-hydroxylation in the rat in vitro and in viva. Food Chem. Toxicol. 44, 1414-1423.
Yeung, J.H.K., Or, P.M.Y., 2011. Polysaccharide peptides from Coriolus versicolor competitively inhibit tolbutamide 4-hydroxylation in specific human CYP2C9 isoform and pooled human liver microsomes. Phytomedicine 18, 1170-1175.
Zhang, J., Tian, Q., Chan, Y.S., Li, S,C., Zhou, S., Duan, W., Zhu, Y.Z., 2005. Metabolism and transport of oxazaphosphorines and the clinical implications. Drug Metab. Rev. 37, 611-703.
Zhang, L.Y., Zhong, Y., Zhou, J., 1999. The observation of PSP decrease 60 cases chemotherapeutical stomach cancer's side effect. in: Yang, Q.Y. (Ed.), Advanced Research in PSP 1999. The Hong Kong Association for Health Care Limited, Hong Kong, p. 328.
Zhou, S., Gao, Y., Jiang, W., Huang, M., Xu, A., Paxton, J.W., 2003. Interactions of herbs with Cytochrome P450. Drug Meta. Rev. 35, 35-98.
Zhou, S., Lim, L.Y., Chowbay, B., 2004. Herbal modulation of P-glycoprotein. Drug Meta. Rev. 36, 57-104.
Zhou, Y.L., Yang, Q.Y., 1999. 1999 Active principles from Coriolus SP. ln: Yang, Q.Y. (Ed.), Advanced Research in PSP. The Hong Kong Association for Health Care Limited, Hong Kong, pp. 111-124.
Table 1a Composition of amino acids present in the peptide portion of PSP. Amino acid Percentage Amino acid Percentage Amino acid Percentage Aspartic 4 Alanine 2.6 Tyrosine 1.5 acid Threonine 2.3 Cysteine 0.9 Phenylalantne 1.5 Serine 3.2 Valine 1.8 Tryptophan 1.7 Glutamic 5.8 Methionine 0.4 Lysine 2.3 acid Praline 1 Isoleudne 2.2 Histidine 0.7 Glyci ne 2.6 Leucine 2.4 Arginine 1.8 (Data from Yeung and Or 2011). Table 1b Composition of sugars present in the polysaccharide portion of PSP. Amino acid Percentage Glucose 74.6 Xylose 4.8 Galactose 2.7 Mannose 1.5 Arabinose 2.4 Rhamnose 4.8
John H.K. Yeung*, Penelope M.Y. Or
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region, China
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|Author:||Yeung, John H.K.; Or, Penelope M.Y.|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||May 1, 2012|
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