• Proceedings of the PSK Conference
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• 2003.10a
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• pp.88-88
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• 2003

The syntheses of different types of stilbenoid libraries have been studied recently. In these courses, the screening of the generated natural product-mimic focused libraries led to the identification of the novel lead compounds for human cytochrome P450 (CYP) lAs, melanin production, and sortase A. A library of trans-stilbene derivatives was prepared through a new efficient solution pahse synthetic pathway and their inhibitory activities were evaluated on human cytochrome P450s(CYP) 1A1, 1A2, and 1B1 to find a potent and selective CYP1 inhibitor. (omitted)

• Journal of the Korean Society of Tobacco Science
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• v.20 no.2
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• pp.178-182
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• 1998

Previously, we showed that acetone enhanced aryl hydrocarbon hydroxylase (AHH) activity in only 3-methylcholanthrene (MC)- or $\beta$-naphtoflavone (BNF)-inducible microsomes of rat liver. In the present study, the possible mechanism underlying acetone action on AHH was investigated in the liver microsomes from MC-pretreated rats. Other n-alkylketones except acetone did not increase AHH activity, which rather decreased significantly with the length of alkyl side chain. Acetone had no effect on the activity of NADPH-cytochrome P450 reductase or inhibited the formation of 3-OH benzo(a)pyrene (B(a)P) in nonenzymatic model ascorbic acid system. However, in cumene hydroperoxide (CuOOH)-supported B(a)P hydroxylation, acetone enhanced its velocity remarkably by 30% at the optimal concentration (30 $\mu$M CuOOH and 1.0% acetone). From these results, we conclude that acetone may facilitate the formation of an activated oxygen species or the insertion of oxygen into B(a)P molecule in CYP1A rich microsomes.

• Toxicological Research
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• v.32 no.3
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• pp.207-213
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• 2016

Although propolis is one of the most popular functional foods for human health, there have been no comprehensive studies of herb-drug interactions through cytochrome P450 (CYP) inhibition. The purpose of this study was to determine the inhibitory effects of propolis on the activities of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 using pooled human liver microsomes (HLMs). Propolis inhibited CYP1A2, CYP2E1 and CYP2C19 with an $IC_{50}$ value of 6.9, 16.8, and $43.1{\mu}g/mL$, respectively, whereas CYP2A6, 2B6, 2C9, 2D6, and 3A4 were unaffected. Based on half-maximal inhibitory concentration shifts between microsomes incubated with and without nicotinamide adenine dinucleotide phosphate, propolis-induced CYP1A2, CYP2C19, and CYP2E1 inhibition was metabolism-independent. To evaluate the interaction potential between propolis and therapeutic drugs, the effects of propolis on metabolism of duloxetine, a serotonin-norepinephrine reuptake inhibitor, were determined in HLMs. CYP1A2 and CYP2D6 are involved in hydroxylation of duloxetine to 4-hydroxy duloxetine, the major metabolite, which was decreased following propolis addition in HLMs. These results raise the possibility of interactions between propolis and therapeutic drugs metabolized by CYP1A2.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.5
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• pp.407-412
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• 2001

Many drugs are primarily metabolized by the cytochrome P450s (CYPs). Drug metabolites would be important allergens for adverse drug reactions such as drug eruptions. Skin tests with a suspected drug have conducted to identify causative drugs of drug eruptions, with vehicles such as white petrolatum, DMSO, ethanol. This study will compare the expression of rat CYP isozyme mRNAs between the skin and the liver, with examining an effect of the vehicles on the cutaneous CYPs using semi-quantitative RT-PCR. Thirty-two Sprague-Dawley rats between the ages of six and eight weeks were divided as four groups. One group was used to compare the constitutive mRNA expression between skin and liver, while the others were to examine the effects of three vehicles. The ratios of expression of CYP1A2, CYP2B1/2, CYP2E1, CYP3A1, and CYP4A1 were significantly higher in the liver than the skin. However, CYP1A1 and CYP2C11 were higher in the skin than liver. The effects of vehicles were quite different; white petrolatum significantly induced CYP1A1 (p=0.012) and CYP2C11 mRNAs, while ethanol inhibited CY P1A1 and CYP2B1/2. DMSO did not make any changes. The results suggest that rat skin can participate in drug metabolism with their own CYP isozymes. The effects of vehicles on the cutaneous CYP expression should not be ignored and may be applied for determination of an appropriate vehicle for certain drug(s).

• Archives of Pharmacal Research
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• v.28 no.10
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• pp.1114-1121
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• 2005

Flavonoids are polyphenols composed of two aromatic rings (A, B) and a heterocyclic ring (C). In order to determine the effects of the number of hydroxyl groups in the B-ring of the flavonoids on human cytochrome P450 (CYP) 1 family enzymes, we evaluated the inhibition of CYP1A-dependent 7-ethoxyresorufin O-deethylation activity by chrysin, apigenin and luteolin, using bacterial membranes that co-express human CYP1A1, CYP1A2, or CYP1B1 with human NADPH-cytochrome P450 reductase. Chrysin, which possesses no hydroxyl groups in its B-ring, exhibited the most pronounced inhibitory effects on CYP1A2-dependent EROD activity, followed by apigenin and luteolin. On the contrary, CYP1A1-mediated EROD activity was most potently inhibited by luteolin, which is characterized by two hydroxyl groups in its B-ring, followed by apigenin and chrysin. However, all of the 5,7-dihydroxyflavones were determined to similarly inhibit CYP1B1 activity. Chrysin, apigenin, and luteolin exhibited a mixed-type mode of inhibition with regard to CYP1A2, CYP1B1, and CYP1A1, with apparent Ki values of 2.4, 0.5, and 2.0 ${\mu}M$, respectively. These findings suggested that the number of hydroxyl groups in the B-ring of 5,7-dihydroxyflavone might have some influence on the degree to which CYP1A enzymes were inhibited, but not on the degree to which CYP1B1 enzymes were inhibited.

• Proceedings of the Korean Society of Toxicology Conference
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• 2002.05a
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• pp.92-92
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• 2002

Recently we have reported that various hydroxystilbenes show strong inhibition of human P450 1 activity. A series of synthetic trans-stilbene derivatives were prepared and their inhibitory potentials were evaluated with the bacterial membrane of recombinant human P450 1A1, 1A2 or 1B1 coexpressed with human P450/NADPH-450 reductase to find new candidates for cancer chemoprevention.(omitted)

• Journal of Life Science
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• v.22 no.8
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• pp.991-998
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• 2012

Ginseng is one of the most commonly used herbal medicines and health foods. Korean red ginseng (KRG; Panax ginseng C.A. Meyer) extract is known to have potential therapeutic activities, such as anti-viral effects, the amelioration of food allergies, anti-oxidant effects, and obesity reduction. Nevertheless, no reports have been issued the modulatory effects of KRG extract on the activity of cytochrome P450 (CYP). In the present study, we investigated the modulatory effect of KRG extract in vitro and in vivo by using pooled human liver microsomes and male ICR mice. When human liver microsomes were incubated with KRG extract at 0.01-10 mg/ml, CYP1A2, 2B6, 2C19, 2D6, and 3A were not significantly inhibited by KRG extract, although CYP2B6 was slightly inhibited. Mice were orally administered KRG extract at 50, 250, or 500 mg/kg daily for 3, 7, or 14 days. However, the activities of CYPs in mouse livers were not significantly different from those of vehicle-treated controls. In conclusion, no significant ginseng-drug interaction was observed. KRG extract did not significantly modulate the activities of CYPs in vitro or in vivo.

• Archives of Pharmacal Research
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• v.25 no.6
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• pp.940-945
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• 2002

The present study was done to determine the effect of trolox C, a hydrophilic analogue of vitamin E, on hepatic injury, especially the alteration in cytochrome P-450 (CYP)-dependent drug metabolism during ischemia and reperfusion (I/R). Rats were subjected to 60 min of hepatic ischemia and 5 h of reperfusion. Rats were treated intravenously with trolox C (2.5 mg/kg) or vehicle (PBS, pH 7.4), 5 min before reperfusion. Serum alanine aminotransferase and lipid peroxidation levels were markedly increased after I/R. This increase was significantly suppressed by trolox C. Cytochrome P-450 content was decreased after I/R but was restored by trolox C. There were no significant differences in ethoxyresorufin O-dealkylase (CYP 1A1) and methoxyresorufin O-dealkylase (CYP 1A2) activities among any of the experimental groups. Pentoxyresorufin O-dealkylase (CYP 2B1) activity was decreased and aniline p-hydroxylase (CYP 2E1) activity was increased after I/R. Both these changes were prevented by trolox C. Our findings suggest that trolox C reduces hepatocellular damage as indicated by abnormalities in microsomal drug-metabolizing function during I/R, and that this protection is, in part, caused by decreased lipid peroxidation.

• Biomolecules & Therapeutics
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• v.16 no.4
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• pp.336-342
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• 2008

The resveratrol analogue piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene) is a polyphenol present in grapes and wine and reported to have anti-carcinogenic activities. To investigate the mechanism of anticarcinogenic activities of piceatannol, the effects on CYP 1 enzymes were determined in Escherichia coli membranes coexpressing recombinant human CYP1A1, CYP1A2 or CYP1B1 with human NADPH-P450 reductase. Piceatannol showed a strong inhibition of CYP1A1 and CYP1B1 in a concentration-dependent manner, and $IC_{50}$ of human CYP1A1 and CYP1B1 was 5.8 ${\mu}M$ and 16.6 ${\mu}M$, respectively. However, piceatannol did not inhibit CYP1A2 activity in the concentration of up to 100 ${\mu}M$. Piceatannol exhibited 3-fold selectivity for CYP1B1 over CYP1A1. The mode of inhibition of piceatannol was non-competitive for CYP1A1 and CYP1B1. The result that piceatannol did not inhibit CYP1B1-mediated $\alpha$-naphthoflavone ($\alpha$-NF) metabolism suggests piceatannol may act as a non-competitive inhibitor as well. In human prostate carcinoma PC-3 cells, piceatannol induces apoptosis and prevents Aktmediated signal pathway. Taken together, abilities of piceatannol to induce apoptotic cell death as well as CYP1 enzyme inhibition make this compound a useful tool for cancer chemoprevention.

• Archives of Pharmacal Research
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• v.26 no.1
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• pp.47-52
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• 2003

The aim of this study was to investigate the effects of trauma on alterations in cytochrome P450 (CYP 450)-dependent drug metabolizing function and to determine the role of Kupffer cells in hepatocellular dysfunction. Rats underwent closed femur fracture (FFx) with associated soft-tissue injury under anesthesia, while control animals received only anesthesia. To deplete Kupffer cells in vivo, gadolinium chloride (GdCl$_3$) was injected intravenously via the tail vein at 7.5 mg/kg body wt., 1 and 2 days prior to FFx surgery. At 72 h after FFx, serum alanine aminotransferase (ALT) activity was increased, and this increase was attenuated by GdCl$_3$ pretreatment. Serum aspartate aminotransferase (AST) and lipid peroxidation levels were not changed by FFx. Hepatic microsomal CYP 450 content and aniline p-hydroxylase (CYP 2E1) activity were significantly decreased; decreases that were not prevented by GdC1$_3$. The level of CYP 2B1 activity was decreased by Kupffer cell inactivation, but not by FFx. There were no significant differences in the activities of CYP 1A1, CYP 1A2 and NADPH-CYP 450 reductase among any of the experimental groups. Our findings suggest that FFx trauma causes mild alterations of hepatic CYP 450-dependent drug metabolism, and that Kupffer cells are not essential for the initiation of such injury.