Induction and Inhibition of Cytochrome P450 and Drug-Metabolizing Enzymes by Climbazole.

Kobayashi, Yasuna; Suzuki, Miyuki; Ohshiro, Naomi; Sunagawa, Takashi; Sasaki, Takeshi; Oguro, Takiko; Tokuyama, Shogo; Yamamoto, Toshinori; Yoshida, Takemi

doi:10.1248/bpb.25.53

Cited by 13 publications

(11 citation statements)

References 30 publications

(17 reference statements)

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“…This study may provide information on the differential effects of simple dipyridyl isomers on hepatic enzymes involved in heme and drug metabolism. In addition, we also found that climbazole potently induced CYP2B1, 3A2 and 4A1, and UGT and GST in rats (Kobayashi et al, 2001(Kobayashi et al, , 2002.…”

Section: Effects Of Nitrogen-containing Compounds On P450 Synthesis Asupporting

confidence: 58%

“…As shown in Table 1, we found that many chemical nitrogen-containing compounds of pyridine and/or imidazole moieties are able to increase P450 content, and some of them also induce ALAS1 in the rat liver, depending on their abilities to induce the hemoproteins (Kobayashi et al, 1992(Kobayashi et al, , 1993a(Kobayashi et al, , 1993b(Kobayashi et al, , 1994(Kobayashi et al, , 2001(Kobayashi et al, , 2002Matsuura et al, 1991;Yoshida et al, 1995). Therefore, it is reasonable to say that P450 inducers are also inducers of ALAS1 in the liver.…”

Section: Effects Of Chemicals On Heme Synthesis and Induction Of P450smentioning

confidence: 90%

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Chemical-induced coordinated and reciprocal changes in heme metabolism, cytochrome P450 synthesis and others in the liver of humans and rodents

2016

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-A wide variety of drugs and chemicals have been shown to produce induction and inhibition of heme-metabolizing enzymes, and of drug-metabolizing enzymes, including cytochrome P450s (P450s, CYPs), which consist of many molecular species with lower substrate specificity. Such chemically induced enzyme alterations are coordinately or reciprocally regulated through the same and/or different signal transductions. From the toxicological point of view, these enzymatic changes sometimes exacerbate inherited diseases, such as precipitation of porphyrogenic attacks, although the induction of these enzymes is dependent on the animal species in response to the differences in the stimuli of the liver, where they are also metabolized by P450s. Since P450s are hemoproteins, their induction and/or inhibition by chemical compounds could be coordinately accompanied by heme synthesis and/or inhibition. This review will take a retrospective view of research works carried out in our department and current findings on chemical-induced changes in hepatic heme metabolism in many places, together with current knowledge. Specifically, current beneficial aspects of induction of heme oxygenase-1, a rate-limiting heme degradation enzyme, and its relation to reciprocal and coordinated changes in P450s, with special reference to CYP2A5, in the liver are discussed. Mechanistic studies are also summarized in relation to current understanding on these aspects. Emphasis is also paid to an example of a single chemical compound that could cause various changes by mediating multiple signal transduction systems. Current toxicological studies have been developing by utilizing a sophisticated "omics" technology and survey integrated changes in the tissues produced by the administration of a chemical, even in time-and dose-dependent manners. Toxicological studies are generally carried out step by step to determine and elucidate mechanisms produced by drugs and chemicals. Such approaches are correct; however, current "omics" technology can clarify overall changes occurring in the cells and tissues after treating animals with drugs and chemicals, integrate them and discuss the results. In the present review, we will discuss chemical-induced similar changes of heme synthesis and degradation, and of P450s and finally convergence to similar or different directions.

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Section: Effects Of Nitrogen-containing Compounds On P450 Synthesis Asupporting

confidence: 58%

Section: Effects Of Chemicals On Heme Synthesis and Induction Of P450smentioning

confidence: 90%

Chemical-induced coordinated and reciprocal changes in heme metabolism, cytochrome P450 synthesis and others in the liver of humans and rodents

2016

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“…Products containing climbazole are widely available in many countries, for example, in Western Europe and China [9]. Climbazole belongs to the group of imidazole fungicides and inhibits the biosynthesis of ergosterol, the major component of fungal plasma membranes, by noncompetitively blocking the active site of the enzyme lanosterol 14a-demethylase, also known as fungal CYP51 [10]. Depending on the dose, climbazole can also induce the production of cytochrome P450 and phase II-metabolizing enzymes in the liver of rats [10].…”

Section: Introductionmentioning

confidence: 99%

“…Climbazole belongs to the group of imidazole fungicides and inhibits the biosynthesis of ergosterol, the major component of fungal plasma membranes, by noncompetitively blocking the active site of the enzyme lanosterol 14a-demethylase, also known as fungal CYP51 [10]. Depending on the dose, climbazole can also induce the production of cytochrome P450 and phase II-metabolizing enzymes in the liver of rats [10]. In efficacy studies it was shown that human toxicity is low for rinse-off application and that genotoxic, teratogenic, or mutagenic effects are unlikely [8,10].…”

Section: Introductionmentioning

confidence: 99%

Ecotoxicity of climbazole, a fungicide contained in antidandruff shampoo

Richter

Wick

Ternes

et al. 2013

Enviro Toxic and Chemistry

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Emerging pollutants such as personal care products can reach the environment via effluents from wastewater treatment plants (WWTPs) and digested sludge. Only recently, the antidandruff agent and antimycotic climbazole was detected for the first time in a WWTP effluent with concentrations up to 0.5 µg/L. Climbazole acts as a C14-demethylase inhibitor (DMI) fungicide and thus has a high efficacy against fungi, but knowledge of its potential environmental impact is lacking. Therefore, the aim of the present study was to characterize climbazole's ecotoxicity by conducting standard biotests with organisms representing different trophic levels from the aquatic as well as the terrestrial ecosystems. It was found that the toxicity of climbazole is mostly similar to that of other DMI fungicides, whereas it proved to be particularly toxic to primary producers. The lowest median effective concentrations (EC50s) were determined for Lemna minor, at 0.013 mg/L (biomass yield), and Avena sativa, at 18.5 mg/kg soil dry weight (shoot biomass). Reduction of frond size in water lentils and shoot length in higher plants suggested an additional plant growth-retarding mode of action of climbazole. In addition, it was demonstrated here that for an ionizable compound such as climbazole, the soil pH can have a considerable influence on phytotoxicity.

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“…CZ has been reported to be quite toxic to aquatic and terrestrial organisms [12,14]. Moreover, azole fungicides like CZ have been regarded as potential endocrine disruptors due to their adverse effects on P450-regulated steroidogenesis [15,16]. Therefore, it is essential to understand the environmental behaviour and dissipation of CZ and its potential risks to organisms.…”

Section: Introductionmentioning

confidence: 99%

Photodegradation of the azole fungicide climbazole by ultraviolet irradiation under different conditions: Kinetics, mechanism and toxicity evaluation

Liu

Ying

Zhao

et al. 2016

Journal of Hazardous Materials

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h i g h l i g h t s• Climbazole (CZ) could be effectively degraded under UV-254 irradiation.• CZ underwent direct and selfsensitized photolysis involving ROS.• The main photodegradation byproducts of CZ were identified and semi-quantitated.• Pathway includes hydroxylative dechlorination, dechlorination, and de-pinacolone.• The toxicity of the photodegradation system reduced after UV-254 irradiation. Keywords: Climbazole Photodegradation Reactive oxygen species By-products Toxicity a b s t r a c t Climbazole (CZ) has been known to persist in various environmental media, and may cause potential risks to aquatic organisms. This study investigated the photodegradation of CZ by ultraviolet (UV, 254 nm) under different conditions. The results revealed that CZ could be effectively degraded in aqueous solutions under UV-254 irradiation with a half-life of 9.78 min (pH = 7.5), and the photodegradation followed pseudo-first-order kinetics. pH had almost no effect on its rate constants and quantum yields; but the water quality of natural waters could affect the photolysis of CZ, and the coexisting constituents such as Fe 3+ , NO 3 − , and HA obviously inhibited its photolysis. The addition of different radical scavengers also inhibited the photodegradation of CZ due to the reduction of reactive oxygen species (ROS). CZ underwent direct and self-sensitized photolysis involving ROS. Based on the identified photodegradation by-products, the proposed pathways included hydroxylative dechlorination, dechlorination and de-pinacolone. Moreover, toxicity evaluation using duckweed found significant toxicity reduction in the photodegradation system of CZ after the irradiation of UV-254, and the remaining by-products did not pose extra toxicity compared with CZ itself. These findings from present study suggest that CZ in effluent could be further reduced by applying UV photolysis treatment.

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Induction and Inhibition of Cytochrome P450 and Drug-Metabolizing Enzymes by Climbazole.

Cited by 13 publications

References 30 publications

Chemical-induced coordinated and reciprocal changes in heme metabolism, cytochrome P450 synthesis and others in the liver of humans and rodents

Chemical-induced coordinated and reciprocal changes in heme metabolism, cytochrome P450 synthesis and others in the liver of humans and rodents

Ecotoxicity of climbazole, a fungicide contained in antidandruff shampoo

Photodegradation of the azole fungicide climbazole by ultraviolet irradiation under different conditions: Kinetics, mechanism and toxicity evaluation

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