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Yoo, Hye Hyun,Lee, Min Woo,Kim, Young Choong,Yun, Chul-Ho,Kim, Dong-Hyun American Society for Pharmacology and Experimental 2007 Drug metabolism and disposition: the biological fa Vol.35 No.10
<P>The inhibition of CYP2A6 by decursinol angelate, a pyranocoumarin isolated from Angelica gigas roots, was examined in human liver microsomes and recombinant CYP2A6. Decursinol angelate moderately inhibited coumarin 7-hydroxylation, but a 20-min preincubation with microsomes and NADPH significantly increased its inhibitory effect (IC(50); >20 versus 4.4 microM). A similar inhibition pattern was observed in nicotine C oxidation, which is also one of the prototype reactions of CYP2A6. Inactivation by decursinol angelate was selective for CYP2A6 and characterized by K(I) values of 0.99 and 2.42 microM and the k(inact) values of 0.136 and 0.053 min(-1) in microsomes and recombinant CYP2A6, respectively. This inactivation was not protected or restored by nucleophiles, reactive oxygen scavengers, or extensive dialysis but was inhibited by the addition of a competitive CYP2A6 inhibitor, pilocarpine. Furthermore, incubation of CYP2A6 with decursinol angelate in the presence of NADPH resulted in a loss of the spectral CYP2A6 content. An in vitro metabolism study revealed that CYP2A6 oxidized decursinol angelate to the dihydrodiol metabolite, presumably via an epoxide intermediate that might be responsible for the inactivation of CYP2A6. These results collectively demonstrated that decursinol angelate inactivated CYP2A6 in a mechanism-based mode.</P>
Park, Seoyoung,Gwak, Jungsug,Cho, Munju,Song, Taeyun,Won, Jaejoon,Kim, Dong-Eun,Shin, Jae-Gook,Oh, Sangtaek American Society for Pharmacology and Experimental 2006 Molecular pharmacology Vol.70 No.3
<P>Aberrant activation of Wnt/beta-catenin signaling and subsequent up-regulation of beta-catenin response transcription (CRT) is a critical event in the development of human colon cancer. Thus, Wnt/beta-catenin signaling is an attractive target for the development of anticancer therapeutics. In this study, we identified hexachlorophene as an inhibitor of Wnt/beta-catenin signaling from cell-based small-molecule screening. Hexachlorophene antagonized CRT that was stimulated by Wnt3a-conditioned medium by promoting the degradation of beta-catenin. This degradation pathway is Siah-1 and adenomatous polyposis colidependent, but glycogen synthase kinase-3beta and F-box beta-transducin repeat-containing protein-independent. In addition, hexachlorophene represses the expression of cyclin D1, which is a known beta-catenin target gene, and inhibits the growth of colon cancer cells. Our findings suggest that hexachlorophene attenuates Wnt/beta-catenin signaling through the Siah-1-mediated beta-catenin degradation.</P>
Byun, Hee Sun,Park, Kyeong Ah,Won, Minho,Yang, Keum-Jin,Shin, Sanghee,Piao, Longzhen,Kwak, Jin Young,Lee, Zee-Won,Park, Jongsun,Seok, Jeong Ho,Liu, Zheng-Gang,Hur, Gang Min American Society for Pharmacology and Experimental 2006 Molecular pharmacology Vol.70 No.3
<P>Protein kinase C (PKC) triggers cellular signals that regulate proliferation or death in a cell- and stimulus-specific manner. Although previous studies have demonstrated that activation of PKC with phorbol 12-myristate 13-acetate (PMA) protects cells from apoptosis induced by a number of mechanisms, including death receptor ligation, little is known about the effect or mechanism of PMA in the necrotic cell death. Here, we demonstrate that PMA-mediated activation of PKC protects against tumor necrosis factor (TNF)-induced necrosis by disrupting formation of the TNF receptor (TNFR)1 signaling complex. Pretreatment with PMA protected L929 cells from TNF-induced necrotic cell death in a PKC-dependent manner, but it did not protect against DNA-damaging agents, including doxorubicin (Adriamycin) and camptothecin. Analysis of the upstream signaling events affected by PMA revealed that it markedly inhibited the TNF-induced recruitment of TNFR1-associated death domain protein (TRADD) and receptor-interacting protein (RIP) to TNFR1, subsequently inhibiting TNF-induced activation of nuclear factor-kappaB and c-Jun NH2-terminal kinase (JNK). However, JNK inhibitors do not significantly affect TNF-induced necrosis, suggesting that the inhibition of JNK activation by PMA is not part of the antinecrotic mechanism. In addition, PMA acted as an antagonist of TNF-induced reactive oxygen species (ROS) production, thereby suppressing activation of ROS-mediated poly(ADP-ribose)polymerase (PARP), and thus inhibiting necrotic cell death. Furthermore, during TNF-induced necrosis, PARP was significantly activated in wild-type mouse embryonic fibroblast (MEF) cells but not in RIP-/- or TNFR-associated factor 2-/-MEF cells. Taken together, these results suggest that PKC activation ensures effective shutdown of the death receptor-mediated necrotic cell death pathway by modulating formation of the death receptor signaling complex.</P>
Kwon, Young Nam,Shin, Sang Mi,Cho, Il Je,Kim, Sang Geon American Society for Pharmacology and Experimental 2009 Drug metabolism and disposition: the biological fa Vol.37 No.6
<P>Oltipraz protects cells from chemical-induced carcinogenesis partly because of phase 2 enzyme induction. Certain oltipraz metabolites also induce phase 2 enzymes. This study investigated the cytoprotective effects of the oxidized metabolites of oltipraz against arachidonic acid (AA), a proinflammatory fatty acid that causes cellular reactive oxygen species (ROS) production and mitochondrial impairment, and the mechanistic basis of their action in HepG2 cells. Treatment with 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one (M1) or 7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]-pyrazine (M2), but not 7-methyl-8-(methylsulfinyl)-6-(methylthio)H-pyrrolo[1,2-a]pyrazine (M3) or 7-methyl-6,8-bis(methylsulfinyl)H-pyrrolo[1,2-a]pyrazine (M4), enabled cells to protect against AA-induced apoptosis. M1 and M2 treatment protected cells from ROS produced by AA and inhibited AA-induced glutathione depletion. Moreover, both M1 and M2 effectively inhibited mitochondrial dysfunction induced by AA, although M2 alone slightly elicited it at a relatively high concentration. M1 and M2 activated AMP-activated protein kinase (AMPK), but M3 and M4 failed to do so. AMPK activation by M1 and M2 contributed to cell survival against AA through a decrease in cellular ROS production and prevention of mitochondrial dysfunction, as shown by the reversal of the metabolites' restoration of mitochondrial membrane potential by compound C treatment or overexpression of a dominant-negative mutant AMPK. Consistently, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, an AMPK activator, also had a cytoprotective and antioxidant effect against AA. Our results demonstrate that, of the major metabolites of oltipraz, M1 and M2 are capable of protecting cells from AA-induced ROS production and mitochondrial dysfunction, which may be associated with AMPK activation.</P>
Kim, Dong-Hyun,Ahn, Taeho,Jung, Heung-Chae,Pan, Jae-Gu,Yun, Chul-Ho American Society for Pharmacology and Experimental 2009 Drug metabolism and disposition: the biological fa Vol.37 No.5
<P>In recent studies, the wild-type and mutant forms of cytochrome P450 (P450) BM3 (CYP102A1) from Bacillus megaterium were found to metabolize various drugs through reactions similar to those catalyzed by human P450 enzymes. Therefore, it was suggested that CYP102A1 can be used to produce large quantities of the metabolites of human P450-catalyzed reactions. trans-Resveratrol (3,4',5-trihydroxystilbene), an anticancer-preventive agent, is oxidized by human P450 1A2 to produce two major metabolites, piceatannol (3,5,3',4'-tetrahydroxystilbene) and another hydroxylated product. In this report, we show that the oxidation of trans-resveratrol, a human P450 1A2 substrate, is catalyzed by wild-type and a set of CYP102A1 mutants. One major hydroxylated product, piceatannol, was produced as a result of the hydroxylation reaction. Other hydroxylated products were not produced. Piceatannol formation was confirmed by high-performance liquid chromatography and gas chromatograph-mass spectrometry by comparing the metabolite with the authentic piceatannol compound. These results demonstrate that CYP102A1 mutants can be used to produce piceatannol, a human metabolite of resveratrol.</P>