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1. List of contributors

Author

Anadón, Arturo, primary, Andrys, Rudolf, additional, Avdonin, Pavel, additional, Bajgar, Jiri, additional, Balali-Mood, Mahdi, additional, Balszuweit, Frank, additional, Banerjee, Atrayee, additional, Bast, Cheryl B., additional, Belinskaia, Daria, additional, Bharti, Vijay K., additional, Bollinger, Claire E., additional, Casillas, Robert P., additional, Clark, Ryan, additional, Clarkson, Edward D., additional, Cole, Toby B., additional, Cope, Rhian B., additional, Coppock, Robert W., additional, Costa, Lucio G., additional, Dettbarn, Wolf-D., additional, Dlabkova, Alzbeta, additional, Doss, Robin B., additional, Dziwenka, Margitta M., additional, Estevez, Jorge, additional, Evans, Tim J., additional, Fink, John K., additional, Flora, Swaran J.S., additional, Furlong, Clement E., additional, Fusek, Josef, additional, Garrick, Jacqueline, additional, Gearhart, Jeffery M., additional, Gerecke, Donald R., additional, Glass-Mattie, Dana F., additional, Goel, Saryu, additional, Goncharov, Nikolay, additional, Gordon, Richard K., additional, Gray, Joshua P., additional, Grubic, Zoran, additional, Gulati, Kavita, additional, Gupta, Ramesh C., additional, Gwaltney-Brant, Sharon M., additional, Hamilton, Tracey A., additional, Harris, Kenneth J., additional, Hood, Darryl B., additional, Jakubowski, Edward M., additional, Jenkins, Richard, additional, Jett, David A., additional, Jiao, Yuqin, additional, John, Harald, additional, Johnson, Nathan H., additional, Jokanović, Milan, additional, Jun, Daniel, additional, Karakashev, Georgy, additional, Kassa, Jiri, additional, Katalinic, Maja, additional, Kehe, Kai, additional, Khlebnikova, Natalia, additional, Kodavanti, Urmila P., additional, Korf, Ekaterina, additional, Koryagina, Nadezhda, additional, Kovač, Bojan, additional, Krishna, Gopala, additional, Krishna, Mayur, additional, Kuca, Kamil, additional, Kumar, Dinesh, additional, Kuroiwa, Yukio, additional, Kuznetsov, Sergey, additional, Kuča, Kamil, additional, Larsen, Joseph C., additional, Leninskiy, Mikhail, additional, Liu, Jing, additional, Lochotzki, Heather, additional, Lockridge, Oksana, additional, Lockwich, Jordana, additional, Loganathan, Bommanna G., additional, Lončar-Stojiljković, Dragana, additional, Lushchekina, Sofya V., additional, Lyman, Megan E., additional, Maguire, Mark, additional, Makhaeva, Galina F., additional, Malik, Jitendra K., additional, Malinak, David, additional, Mars, Tomaz, additional, Marsillach, Judit, additional, Martínez-Larrañaga, María-Rosa, additional, Masson, Patrick, additional, Masunaga, Shigeki, additional, McCallister, Monique, additional, McCauley, Linda A., additional, McClellan, Roger O., additional, McNutt, Patrick M., additional, Meek, Edward C., additional, Merrill, Elaine, additional, Milanez, Sylvia, additional, Mindukshev, Igor, additional, Mis, Katarina, additional, Misik, Jan, additional, Murphy, Michael J., additional, Musilek, Kamil, additional, Nakajima, Tamie, additional, Nelson, Marian R., additional, Nepovimova, Eugenie, additional, Okumura, Tetsu, additional, Patocka, Jiri, additional, Pegan, Katarina, additional, Pejchal, Jaroslav, additional, Pirkmajer, Sergej, additional, Pita, René, additional, Pitt, Jason, additional, Pitt, Yiuka, additional, Platoff, Gennady E., additional, Pope, Carey N., additional, Radilov, Andrey, additional, Rahal, Anu, additional, Ramesh, Aramandla, additional, Ray, Arunabha, additional, Rembovskiy, Vladimir, additional, Rhoades, Raina, additional, Richardson, Rudy J., additional, Ristić, Dragana, additional, Robinson, Peter J., additional, Romero, Alejandro, additional, Ruark, Chris, additional, Salem, Harry, additional, Samchenko, Natalia, additional, Satoh, Tetsuo, additional, Savage, Russell E., additional, Savelieva, Elena, additional, Schopfer, Lawrence M., additional, Sciuto, Alfred M., additional, Seto, Yasuo, additional, Shakarjian, Michael P., additional, Shmurak, Vladimir, additional, Skarka, Adam, additional, Škrbić, Ranko, additional, Sogorb, Miguel, additional, Spriggs, Shardell M., additional, Srivastava, Sakshi, additional, Steinritz, Dirk, additional, Stojiljković, Miloš P., additional, Tewari-Singh, Neera, additional, Thiermann, Horst, additional, Thokchom, Suresh Kumar, additional, Thompson, Larry J., additional, Ukolov, Anton, additional, Valerio, Luis G., additional, van der Schans, M.J., additional, Varma, Daya R., additional, Vilanova, Eugenio, additional, Watson, Annetta, additional, Wijeyesakere, Sanjeeva J., additional, Wismer, Tina, additional, Worden, R. Mark, additional, Worek, Franz, additional, Wright, Linzzi K., additional, Yamasue, Hidenori, additional, Yoshida, Takemi, additional, Yoshioka, Toshiharu, additional, Young, Robert A., additional, Zaja-Milatovic, Snjezana, additional, Zinchenko, Valeriy, additional, and Zoltani, Csaba K., additional

Published
2020
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4. Derivatization-assisted immunoassays: application for group-specific detection of potent methamphetamine and amphetamine enantiomers

Author

Morita, Izumi, primary, Kiguchi, Yuki, additional, Oyama, Hiroyuki, additional, Yamaki, Kouya, additional, Sakio, Nami, additional, Kashiwabara, Keisuke, additional, Kuroda, Yumi, additional, Ito, Aya, additional, Yokota, Asaka, additional, Ikeda, Natsumi, additional, Kikura-Hanajiri, Ruri, additional, Ueda, Hiroshi, additional, Numazawa, Satoshi, additional, Yoshida, Takemi, additional, and Kobayashi, Norihiro, additional

Published
2022
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5. List of Contributors

Author

Anadón, Arturo, primary, Anderson, Jaime, additional, Anzai, Jun-ichi, additional, Aschner, Michael, additional, Avdonin, Pavel, additional, Bajgar, Jiri, additional, Bakshi, Kulbir, additional, Balali-Mood, Mahdi, additional, Balszuweit, Frank, additional, Banerjee, Atrayee, additional, Bast, Cheryl B., additional, Bhattacharya, Rahul, additional, Bollinger, Claire E., additional, Casillas, Robert P., additional, Chemtob, Sylvain, additional, Clark, Ryan, additional, Clarkson, Edward D., additional, Cole, Toby B., additional, Coppock, Robert W., additional, Costa, Lucio G., additional, Dettbarn, Wolf-D., additional, Dobbins, Dorothy L., additional, Dorsey, Russell, additional, Dziwenka, Margitta, additional, Emmett, George, additional, Estévez, Jorge, additional, Evans, Timothy J., additional, Fink, John K., additional, Flora, Swaran J.S., additional, Fonnum, Frode, additional, Furlong, Clement E., additional, Fusek, Josef, additional, Gearhart, Jeffery M., additional, Gerecke, Donald R., additional, Glass-Mattie, Dana F., additional, Goel, Saryu, additional, Goncharov, Nikolay, additional, Gordon, Richard K., additional, Gray, Joshua P., additional, Grubic, Zoran, additional, Gulati, Kavita, additional, Gupta, Ramesh C., additional, Gwaltney-Brant, Sharon M., additional, Hamilton, Tracey L., additional, Hauschild, Veronique, additional, Hein, Nichole D., additional, Hilmas, Corey J., additional, Hilmas, Elora, additional, Hood, Darryl B., additional, Jakubowski, Edward M., additional, Jenkins, Richard O., additional, Jett, David A., additional, Jiang, George C-T, additional, Jiao, Yuqin, additional, John, Harald, additional, Johnson, Nathan H., additional, Jokanović, Milan, additional, Jun, Daniel, additional, Kadakkuzha, Beena M., additional, Kassa, Jiri, additional, Katalinic, Maja, additional, Kehe, Kai, additional, Khlebnikova, Natalia, additional, King, Joseph, additional, Kodavanti, Urmila P., additional, Korabecny, Jan, additional, Krishna, Gopala, additional, Krivorotova, Nadezhda, additional, Kuca, Kamil, additional, Kuroiwa, Yukio, additional, Kuznetsov, Anatoliy, additional, Kuznetsov, Sergey, additional, Larsen, Joseph C., additional, Leung, Yiuka, additional, Liu, Jing, additional, Liu, Xin-an, additional, Lockridge, Oksana, additional, Loganathan, Bommanna G., additional, Lugo, Andres M., additional, Maguire, Mark, additional, Makhaeva, Galina F., additional, Malik, Jitendra K., additional, Mars, Tomaz, additional, Martínez-Larrañaga, Maria Rosa, additional, Masson, Patrick, additional, Masunaga, Shigeki, additional, McCallister, Monique, additional, McCauley, Linda A., additional, McNutt, Patrick M., additional, Meek, Edward, additional, Merrill, Elaine, additional, Milanez, Sylvia, additional, Mindukshev, Igor, additional, Mis, Katarina, additional, Mulay, Shree, additional, Murphy, Michael J., additional, Musilek, Kamil, additional, Myhrer, Trond, additional, Okumura, Tetsu, additional, Opresko, Dennis, additional, Orlova, Tatiana, additional, Pål, Aas, additional, Pan, Xiaoping, additional, Patocka, Jiri, additional, Pirkmajer, Sergej, additional, Pita, Rene, additional, Pitt, Jason, additional, Pope, Carey, additional, Prokofieva, Daria, additional, Radilov, Andrey, additional, Ramaiah, Shashi K., additional, Ramesh, Aramandla, additional, Ray, Arunabha, additional, Ray, Kausik, additional, Rembovskiy, Vladimir, additional, Rhoades, Raina, additional, Richardson, Rudy J., additional, Rizzo, Valerio, additional, Robinson, Peter J., additional, Ruark, Chris, additional, Salem, Harry, additional, Satoh, Tetsuo, additional, Savage, Russell E., additional, Savelieva, Elena, additional, Schopfer, Lawrence M., additional, Sciuto, Alfred M., additional, Seto, Yasuo, additional, Shakarjian, Michael P., additional, Sogorb, Miguel, additional, Soreq, Hermona, additional, Sterri, Sigrun Hanne, additional, Stick, Melissa, additional, Suzuki, Kouichiro, additional, Taki, Kenji, additional, Thiermann, Horst, additional, Thompson, Larry J., additional, Uchea, Chibuzor, additional, Ukolov, Anton, additional, Valerio, Luis G., additional, Van der Merwe, Deon, additional, van der Schans, Marcel J., additional, Varma, Daya R., additional, Vilanova, Eugenio, additional, Vinokurov, Maxim, additional, Voitenko, Natalia, additional, Waiskopf, Nir, additional, Watson, Annetta, additional, Wijeyesakere, Sanjeeva J., additional, Wismer, Tina, additional, Woltjer, Randall L., additional, Mark Worden, R., additional, Worek, Franz, additional, Wright, Linnzi, additional, Yeung, David T., additional, Yoshida, Takemi, additional, Young, Robert A., additional, Zaja-Milatovic, Snjezana, additional, Zinchenko, Valeriy, additional, and Zoltani, Csaba K., additional

Published
2015
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6. The Tokyo Subway Sarin Attack

Author

Okumura, Tetsu, primary, Taki, Kenji, additional, Suzuki, Kouichiro, additional, Yoshida, Takemi, additional, Kuroiwa, Yukio, additional, and Satoh, Tetsuo, additional

Published
2015
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11. Regulation of the susceptibility to oxidative stress by cysteine availability in pancreatic [beta]-cells

Author

Numazawa, Satoshi, Sakaguchi, Harumi, Aoki, Risa, Taira, Toshio, and Yoshida, Takemi

Subjects
Oxidative stress -- Risk factors, Cysteine -- Influence, Cysteine -- Properties, Pancreatic beta cells -- Properties, Glutathione -- Health aspects, Hydrogen peroxide -- Health aspects, Biological sciences
Abstract

Pancreatic 13-cells are susceptible to oxidative stress, which is related closely to the islet dysfunction. In the present study, using the pancreatic cell lines HIT-T15 and RINm5F as known in vitro models of impaired [beta]-cell function as well as primary rat islet [beta]-cells, we observed a relationship between intracellular glutathione levels and oxidative stress-mediated cell dysfunction. Hydrogen peroxide and 4-hydroxy2-nonenal caused cell death in HIT-T15 and RINm5F cells at lower concentrations compared with non-[beta]-cells, such as HepG2 and NRK49F cells. The extent of the cytotoxicity caused by the model oxidants was inversely correlated well with intracellular glutathione levels in the cell lines used. Treatment of HIT-T15 and RINm5F cells with L-cysteine or L-cystine significantly augmented the glutathione contents, surpassing the effect of N-acetylcysteine, and abrogated 4-hydroxy-2-nonenal-mediated cytotoxicity almost completely. L-Cysteine increased intracellular glutathione levels in primary [beta]-cells as well. Supplementation of L-cysteine to the RINm5F cell culture inhibited 4-hydroxy-2-nonenal-mediated cytosolic translocation of PDX-1, a key transcription factor for [beta]-cell function. Intrinsic transport activities ([V.sub.max]/[K.sub.m]) of the L-cystine/L-glutamate exchanger in HIT-T15 and RINm5F cells were considerably lower than that in NRK-49F cells, although gene expressions of the exchanger were similar in these cells. Results obtained from the present study suggest that the restricted activity of the L-cystine/L-glutamate exchanger controls the levels of intracellular glutathione, thereby making [beta]-cells become susceptible to oxidative stress. system [x.sup.-.sub.c]; glutathione; hydrogen peroxide; reactive oxygen species; PDX-1

Published
2008

15. Titanium niobate and titanium tantalite nanosheets as strong solid acid catalysts

Author

Takagaki, Atsushi, Yoshida, Takemi, Lu, Darling, Kondo, Junko N., Hara, Michikazu, Domen, Kazunari, and Hayashi, Shigenobu

Subjects
Hydrolysis -- Methods, Acetic acid -- Atomic properties, Titanium compounds -- Atomic properties, Chemicals, plastics and rubber industries
Abstract

HTiNbO5, HTi2NbO7 and HTiTaO5 nanosheet, prepared by exfoliation of protonated cation-exchangeable layered metal oxides, function as strong solid acids for the esterification of acetic acid and hydrolysis of ethyl acetate, acid-catalyzed reactions. The acid catalytic activity of these titanium niobate/tantalate nanosheets analyzed by H1 magic-angle-spinning nuclear magnetic resonance spectroscopy (H1 MAS NMR), revealed the presence of strong Bronsted active sites in the form of bridging hydroxyl groups.

Published
2004

19. Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress

Author

Numazawa, Satoshi, Ishikawa, Makie, Yoshida, Aya, Tanaka, Sachiko, and Yoshida, Takemi

Subjects
Protein kinases -- Research, Physiology -- Research, Biological sciences
Abstract

Transcription factor NF-E2-related factor 2 (Nrf2) regulates the induction of antioxidative proteins, including heme oxygenase-1 (HO-1). Nrf2 is sequestered in the cytoplasm by Keap1 under unstimulated conditions but translocates into the nucleus and transactivates the antioxidant responsive element (ARE) upon exposure to oxidative insults. It has recently been demonstrated that in vitro phosphorylation of Nrf2 on Ser40 by protein kinase C (PKC) facilitates the dissociation of Nrf2 from the Keap1 complex (Huang HC, Nguyen T, and Pickett CB. J Biol Chem 277: 42769-42774, 2002). The present study was designed to examine whether PKC is involved in oxidative stress-mediated nuclear translocation of Nrf2 in vivo and, if so, which PKC isoforms are involved. Induction of HO-1 gene expression by phorone, a glutathione depletor, and 4-hydroxy-2,3-nonenal (4-HNE), an end product of lipid peroxidation, was suppressed by a specific PKC inhibitor, Ro-31-8220, at concentrations that inhibit all isoforms in WI-38 cells. The induction of HO-1 was not affected by prolonged exposure of the cells to 12-O-tetradecanoylphorbol-13 acetate (TPA), suggesting that TPA-insensitive atypical PKC (aPKC) isoforms are involved. An immunocomplex kinase assay revealed that phorone and 4-HNE increased aPKCi activity. In COS-7 cells, 4-HNE induced nuclear translocation of the Nrf2-green fluorescent protein (GFP) fusion protein, but not the Nrf2(S40A)-GFP mutant. In the absence of oxidative insults, the Nrf2(S40E)-GFP mutant was distributed in the nucleus. The Nrf2-GFP accumulation in the nucleus was induced by coexpression of aPKCL, but not by a kinase inactive mutant aPKCi(K274W). The activity of an ARE-driven reporter was increased by coexpression of aPKCi, and this effect was eliminated by Ro-31-8220 in HepG2 cells. The reporter activity induced by 4-HNE was inhibited by coexpression of aPKCi(K274W). These results suggest that phosphorylation of Nrf2 Ser40 by aPKC(s) is involved in the nuclear translocation and ARE transactivation of Nrf2 by oxidative stress. heme oxygenase-1; nuclear translocation; phosphorylation; NF-E2-related factor 2

Published
2003

27. Forensic immunochemistry.

Author

Aoki, Kimiko, Yoshida, Takemi, and Kuroiwa, Yukio

Subjects
Radioimmunoassay -- Usage, Enzyme-linked immunosorbent assay -- Usage, Immunochemistry -- Analysis
Published
1996

33. Alpha7 nicotinic ACh receptor mediated neuroprotective action by nicotine and GTS-21: An approach by the hippocampal organotypic slice cultures

Author

ITOH, Yoshitsugu, TANAKA, Sachiko, TAKAHASHI, Sayaka, MORIKWA, Chikara, NUMAZAWA, Satoshi, KAIZAKI, Asuka, and YOSHIDA, Takemi

Subjects
nervous system
Abstract

Nicotine, main constituent of tabaco, is known as a nicotinic acetylcholine receptor (nAChR) agonist and increases cognitive performance. 3-(2,4-dimethoxybenzylidene)-anabaseine (GTS-21) is derived from the marine worm toxin, anabaseine, and is alpha7-selective nAChR (D7-nAChR) agonist. Both nicotine and GTS-21 were expected as therapeutic agents of Alzheimer’s disease. Several studies showed that nicotine and GTS-21 protected neuron by activating nAChR, especially D7-nAChR. It has been reported that D7-nAChR has been shown to be an essential regulator of inflammation. The purpose of this study is to examine the neuroprotective and anti-inflammatory effects of nicotine and GTS-21 using organotypic hippocampal slice cultures. Kainic acid (KA, 5-50µM) induced concentration- and time-dependent neuronal cell death in the hippocampal organotypic slice cultures. The pretreatment with nicotine and GTS-21 tended to decrease in KA toxicity. In a CA3 area-specific analysis, pretreatment with nicotine resulted in significant inhibition of KA-induced neurotoxicity. The results suggest that nicotine may protect KA-induced neuronal cell death via D7-nAChR. We also examined anti-inflammatory effects of nicotine and GTS-21. Hippocampal slices were pretreated with nicotine or GTS-21, and then treated with lipopolysaccharide (LPS). LPS treatment induced concentration-dependent increases in TNFD and IL-1E gene expressions. LPS-induced TNFD gene expression, but not IL-1E was suppressed by GTS-21 pretreatment. These results suggest that D7-nAChR might be involved in the microglia activation towards a neuroprotective role by suppressing inflammatory cytokine.

Published
2011

34. Distinct PKC isozymes regulate bufalin-induced differentiation and apoptosis in human monocytic cells

Author

KUROSAWA, MASAHIRO, TANI, YOSHIHIRO, NISHIMURA, SATOSHI, NUMAZAWA, SATOSHI, and YOSHIDA, TAKEMI

Subjects
Isoenzymes -- Physiological aspects, Cell differentiation -- Physiological aspects, Cell death -- Physiological aspects, Monocytic leukemia -- Physiological aspects, Protein kinases -- Physiological aspects, Gene expression -- Physiological aspects, Biological sciences
Abstract

Kurosawa, Masahiro, Yoshihiro Tani, Satoshi Nishimura, Satoshi Numazawa, and Takemi Yoshida. Distinct PKC isozymes regulate bufalin-induced differentiation and apoptosis in human monocytic cells. Am J Physiol Cell Physiol 280: C459-C464, 2001.--Bufalin, an [Na.sup.+]-[K.sup.+]-ATPase inhibitor, simultaneously induced cell differentiation and apoptosis in human monocytic leukemia THP-1 cells. In this study, we investigated the regulatory role of protein kinase C (PKC) isozymes in bufalin-induced cell differentiation and apoptosis. A PKC-specific but isozyme-nonselective inhibitor, Ro-31-8220, and a cPKC selective inhibitor, Go-6976, caused significant attenuation of bufalin-induced interleukin- 1[Beta] (IL-1[Beta]) gene expression, a mature monocytic marker, indicating that cPKC participates in the bufalin-induced cell differentiation. On the other hand, cPKC[Beta]- and nPKC[Delta]-defective THP-1/TPA cells displayed strong resistance to the bufalin-induced DNA ladder formation. Rottlerin, an nPKC[Delta]-specific inhibitor, partially attenuated preapoptotic effects of bufalin, such as the limited proteolysis of nPKC[Delta] and poly(ADP-ribose) polymerase and the cell staining by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, suggesting that nPKC[Delta] is involved, at least in part, in bufalin-induced apoptosis. In contrast, G5-6976 and rottlerin significantly augmented bufalin-induced apoptosis and differentiation, respectively. The findings suggest that bufalin-induced cell differentiation and apoptosis are interlinked and that distinct PKC isozymes are involved in the fate of the cell. cell differentiation; apoptosis

Published
2001

35. ERK signaling mediates the induction of inflammatory cytokines by bufalin in human monocytic cells

Author

KUROSAWA, MASAHIRO, NUMAZAWA, SATOSHI, TANI, YOSHIHIRO, and YOSHIDA, TAKEMI

Subjects
Physiology -- Research, Interleukin-1 -- Research, Cell differentiation -- Analysis, Gene expression -- Research, Cellular signal transduction -- Research, Protein kinases -- Research, Biological sciences
Abstract

Kurosawa, Masahiro, Satoshi Numazawa, Yoshihiro Tani, and Takemi Yoshida. ERK signaling mediates the induction of inflammatory cytokines by bufalin in human monocytic cells. Am. J. Physiol. Cell Physiol. 278: C500-C508, 2000.--Treatment of human leukemia THP-1 cells with bufalin, a specific inhibitor of [Na.sup.+]-[K.sup.+]-ATPase, sequentially induces c-fos and inflammatory cytokines interleukin-1[Beta] (IL-1[Beta]) and tumor necrosis factor-[Alpha] (TNF-[Alpha]) gene expressions before the appearance of mature phenotypes of monocytic cells. In this study we examined the signal transduction leading to bufalin-induced gene expressions. Bufalin selectively activated extracellular signal-regulated kinase (ERK), compared with other mitogen-activated protein (MAP) kinase family members. Pretreatment of THP-1 cells with PD-98059, an inhibitor of the ERK-kinase cascade, abolished bufalin-induced c-fos and IL-1[Beta] gene expressions, indicating that the ERK-kinase cascade mediates the induction of inflammatory cytokines by bufalin. Inhibition of the [Na.sup.+]/ [Ca.sup.2+] exchanger by KB-R7943 and of protein kinase C (PKC) by Ro-31-8220 suppressed ERK activation and gene expressions of c-fos and IL-1[Beta]. These findings suggest that [Na.sup.+]-[K.sup.+] ATPase inhibition by bufalin induces calcium influx and thereby activates PKC and ERK. In cells treated with an inhibitor of p38 MAP kinases, SB-203580, bufalin-mediated ERK activation became persistent and the induction of IL-1[Beta] and TNF-[Alpha] expressions was significantly augmented. These results suggest that cross talk in bufalin-mediated ERK activation is negatively regulated by endogenous p38 MAP kinase activations. interleukin-1[Beta]; sodium-potassium-adenosinetriphosphatase; cell differentiation; extracellular signal-regulated kinase

Published
2000

39. Structure-activity relationships in the induction of hepatic microsomal cytochrome P450 by clotrimazole and its structurally related compounds in rats

Author

Tobinaga Seisho, Yoshida Takemi, Fukuda Teruo, Matsuura Yoichi, Kotani Eiichi, Iio Toshihiro, and Kuroiwa Yukio

Subjects
Male, Cytochrome, Stereochemistry, Triazole, Biochemistry, Structure-Activity Relationship, chemistry.chemical_compound, Cytochrome P-450 Enzyme System, medicine, Animals, Imidazole, Moiety, Clotrimazole, Pharmacology, biology, Cytochrome c, Imidazoles, Cytochrome P450, Rats, Inbred Strains, Rats, chemistry, Enzyme Induction, Microsomes, Liver, biology.protein, Microsome, medicine.drug
Abstract

We investigated the structure-activity relationship in the induction of hepatic microsomal cytochrome P450 by clotrimazole and its structurally related compounds. For this purpose, we synthesized various compounds structurally analogous to clotrimazole and injected them into rats at a fixed dose of 0.2 mmol/kg. We found that the chlorine atom in clotrimazole was not necessary for the induction of cytochrome P450. The imidazole moiety of clotrimazole, however, was a very important structural component for the induction of cytochrome P450; triazole, but not pyrrole, could be substituted for this moiety. 1-Tritylimidazole, 1-diphenylmethylimidazole and 1-benzylimidazole were also found to be inducers of cytochrome P450, but, to a somewhat lesser extent, with a decreasing number of substituted phenyl groups. Thus, 1-benzylimidazole was a minimum structurally active unit for inducing cytochrome P450. In addition, 4-diphenylmethylpyridine and 4-benzylpyridine also induced cytochrome P450 to extents similar to those induced by the corresponding imidazole derivatives, but 4-benzylpiperidine lacked this effect. When the methylene unit of clotrimazole-related compounds was introduced by a hydroxy or amino group instead of imidazole, there was a less extensive increase in cytochrome P450 content. This inducing effect was lost completely by the lack of an imidazole moiety and imidazole itself. 1-Phenylethylimidazole and 1-benzylimidazole induced cytochrome P450 to a similar extent. All of these findings suggest that 1-substituted heteroaromatic compounds having two or more nitrogen atoms are likely to be required for inducing cytochrome P450. Immunoblot analysis revealed that clotrimazole and other various inducers found in this study increased cytochrome P450b/e content. These results could provide information on the effects of drugs and chemicals on cytochrome P450 induction.

Published
1991

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