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Article ; Online: Changes in the expression of drug-metabolising enzymes and drug transporters in mice with collagen antibody-induced arthritis.

Fujino, Chieri / Ueshima, Satoshi / Katsura, Toshiya

Xenobiotica; the fate of foreign compounds in biological systems

2022 Volume 52, Issue 7, Page(s) 758–766

Abstract: 1. We investigated the changes in the expression of drug-metabolising enzymes and drug transporters in the liver, small intestine and kidney of mice with collagen antibody-induced arthritis (CAIA) to determine whether changes in these expressions affect ... ...

Abstract	1. We investigated the changes in the expression of drug-metabolising enzymes and drug transporters in the liver, small intestine and kidney of mice with collagen antibody-induced arthritis (CAIA) to determine whether changes in these expressions affect pharmacokinetics of drugs in patients with rheumatoid arthritis.2. mRNA expression levels of cytochrome P450 (Cyp) 2b10, Cyp2c29 and Cyp3a11 were observed to be lower in the liver and small intestine of CAIA mice than in control mice. Compared with control mice, mRNA expression levels of multidrug resistance 1 b, peptide transporter 2 and organic anion transporter (Oat) 2 were high in the liver of CAIA mice. Changes in these expression levels were different among organs. However, elevated expression of Oat2 mRNA was not associated with an increase in protein expression and transport activity evaluated using [
MeSH term(s)	Mice ; Animals ; Arthritis, Rheumatoid ; Collagen
Chemical Substances	Collagen (9007-34-5)
Language	English
Publishing date	2022-10-27
Publishing country	England
Document type	Journal Article
ZDB-ID	120287-x
ISSN	1366-5928 ; 0049-8254
ISSN (online)	1366-5928
ISSN	0049-8254
DOI	10.1080/00498254.2022.2137442
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Zs.A 782: Show issues

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Article ; Online: Attenuation of phenobarbital-induced cytochrome P450 expression in carbon tetrachloride-induced hepatitis in mice models.

Fujino, Chieri / Kuzu, Taiki / Kubo, Yukine / Hayashi, Kurumi / Ueshima, Satoshi / Katsura, Toshiya

Biopharmaceutics & drug disposition

2023 Volume 44, Issue 5, Page(s) 351–357

Abstract: Certain pathological conditions, such as inflammation, are known to affect basal cytochrome P450 (CYP) expression by modulating transcriptional regulation, and the pharmacokinetics of drugs can vary among patients. However, changes in drug-induced CYP ... ...

Abstract	Certain pathological conditions, such as inflammation, are known to affect basal cytochrome P450 (CYP) expression by modulating transcriptional regulation, and the pharmacokinetics of drugs can vary among patients. However, changes in drug-induced CYP expression under pathological conditions have not been elucidated in detail. Here, we investigated the effects of hepatic inflammation and injury on phenobarbital-induced expression of CYP isoforms in mice. Phenobarbital was administered once as a CYP inducer in the carbon tetrachloride-induced hepatitis model mice. The mRNA expression levels of Cyp3a11 and Cyp2b10 in the liver and small intestine were measured using reverse transcription polymerase chain reaction. The enzymatic activity of CYP3A in liver S9 was evaluated using midazolam as the substrate. Phenobarbital increased the mRNA expression of Cyp3a11 and Cyp2b10 in the liver of healthy mice, but not in the small intestine. Increased mRNA expression of hepatic Cyp3a11 and Cyp2b10 by phenobarbital was significantly suppressed in the hepatitis model mice. Hepatitis also suppressed the increased CYP3A enzymatic activity induced by phenobarbital in liver S9, consistent with the results of Cyp3a11 mRNA expression. These results suggest that the inducibility of CYP by phenobarbital may vary in patients with hepatitis, indicating that pharmacokinetic drug-drug interactions can be altered under certain pathological conditions.
MeSH term(s)	Mice ; Humans ; Animals ; Carbon Tetrachloride/metabolism ; Carbon Tetrachloride/pharmacology ; Cytochrome P-450 CYP3A/genetics ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/metabolism ; Phenobarbital/pharmacology ; Phenobarbital/metabolism ; Liver/metabolism ; Gene Expression Regulation, Enzymologic ; Hepatitis/metabolism ; Inflammation/metabolism ; RNA, Messenger/metabolism
Chemical Substances	Carbon Tetrachloride (CL2T97X0V0) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Phenobarbital (YQE403BP4D) ; RNA, Messenger
Language	English
Publishing date	2023-04-09
Publishing country	England
Document type	Journal Article
ZDB-ID	603014-2
ISSN	1099-081X ; 0142-2782
ISSN (online)	1099-081X
ISSN	0142-2782
DOI	10.1002/bdd.2356
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Zs.A 1520: Show issues

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Article ; Online: Variation in Expression of Cytochrome P450 3A Isoforms and Toxicological Effects: Endo- and Exogenous Substances as Regulatory Factors and Substrates.

Fujino, Chieri / Sanoh, Seigo / Katsura, Toshiya

Biological & pharmaceutical bulletin

2021 Volume 44, Issue 11, Page(s) 1617–1634

Abstract: The CYP3A subfamily, which includes isoforms CYP3A4, CYP3A5, and CYP3A7 in humans, plays important roles in the metabolism of various endogenous and exogenous substances. Gene and protein expression of CYP3A4, CYP3A5, and CYP3A7 show large inter- ... ...

Abstract	The CYP3A subfamily, which includes isoforms CYP3A4, CYP3A5, and CYP3A7 in humans, plays important roles in the metabolism of various endogenous and exogenous substances. Gene and protein expression of CYP3A4, CYP3A5, and CYP3A7 show large inter-individual differences, which are caused by many endogenous and exogenous factors. Inter-individual differences can cause negative outcomes, such as adverse drug events and disease development. Therefore, it is important to understand the variations in CYP3A expression caused by endo- and exogenous factors, as well as the variation in the metabolism and kinetics of endo- and exogenous substrates. In this review, we summarize the factors regulating CYP3A expression, such as bile acids, hormones, microRNA, inflammatory cytokines, drugs, environmental chemicals, and dietary factors. In addition, variations in CYP3A expression under pathological conditions, such as coronavirus disease 2019 and liver diseases, are described as examples of the physiological effects of endogenous factors. We also summarize endogenous and exogenous substrates metabolized by CYP3A isoforms, such as cholesterol, bile acids, hormones, arachidonic acid, vitamin D, and drugs. The relationship between the changes in the kinetics of these substrates and the toxicological effects in our bodies are discussed. The usefulness of these substrates and metabolites as endogenous biomarkers for CYP3A activity is also discussed. Notably, we focused on discrimination between CYP3A4, CYP3A5, and CYP3A7 to understand inter-individual differences in CYP3A expression and function.
MeSH term(s)	Animals ; COVID-19/metabolism ; Cytochrome P-450 CYP3A/metabolism ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/physiology ; Humans ; Liver Diseases/metabolism ; Protein Isoforms/metabolism
Chemical Substances	Protein Isoforms ; Cytochrome P-450 CYP3A (EC 1.14.14.1)
Language	English
Publishing date	2021-11-01
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	1150271-x
ISSN	1347-5215 ; 0918-6158
ISSN (online)	1347-5215
ISSN	0918-6158
DOI	10.1248/bpb.b21-00332
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Zs.A 1474: Show issues

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Article ; Online: Coordinated cytochrome P450 expression in mouse liver and intestine under different dietary conditions during liver regeneration after partial hepatectomy.

Fujino, Chieri / Sanoh, Seigo / Tateno, Chise / Ohta, Shigeru / Kotake, Yaichiro

Toxicology and applied pharmacology

2019 Volume 370, Page(s) 133–144

Abstract: Liver resection is performed to remove tumors in patients with liver cancer, but the procedure's suitability depends on the regenerative ability of the liver. It is important to consider the effects of exogenous factors, such as diets, on liver ... ...

Abstract	Liver resection is performed to remove tumors in patients with liver cancer, but the procedure's suitability depends on the regenerative ability of the liver. It is important to consider the effects of exogenous factors, such as diets, on liver regeneration for the recovery of function. The evaluation of drug metabolism during liver regeneration is also necessary because liver dysfunction is generally observed after the operation. Here, we investigated the influence of a purified diet (AIN-93G) on liver regeneration and changes in the mRNA expression of several cytochrome P450 (CYP) isoforms in the liver and small intestine using a two-thirds partial hepatectomy (PH) mouse model fed with a standard diet (MF) and a purified diet. Liver regeneration was significantly delayed in the purified diet group relative to that in the standard diet group. The liver Cyp2c55 and Cyp3a11 expression was increased at 3 day after PH especially in the purified diet group. Bile acid may partly cause the differences in liver regeneration and CYP expression between two types of diets. On the other hand, Cyp3a13 expression in the small intestine was transiently increased at day 1 after PH in both diet groups. The findings suggest that compensatory induction of the CYP expression occurred in the small intestine after attenuation of drug metabolism potential in the liver. The present results highlight the importance of the relationship between liver regeneration, drug metabolism, and exogenous factors for the effective treatment, including surgery and medication, in patients after liver resection or transplantation.
MeSH term(s)	Animals ; Bile Acids and Salts/blood ; Cytochrome P-450 CYP3A/genetics ; Cytochrome P-450 Enzyme System/genetics ; Diet ; Gene Expression ; Hepatectomy ; Intestines/enzymology ; Isoenzymes/genetics ; Liver/enzymology ; Liver Regeneration/physiology ; Male ; Membrane Proteins/genetics ; Mice ; Mice, Inbred C57BL ; RNA, Messenger/analysis
Chemical Substances	Bile Acids and Salts ; Isoenzymes ; Membrane Proteins ; RNA, Messenger ; Cytochrome P-450 Enzyme System (9035-51-2) ; Cyp3a13 protein, mouse (EC 1.14.14.1) ; Cytochrome P-450 CYP3A (EC 1.14.14.1)
Language	English
Publishing date	2019-03-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2019.03.010
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Zs.B 14: Show issues

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Article: Activation of PXR, CAR and PPARα by pyrethroid pesticides and the effect of metabolism by rat liver microsomes.

Fujino, Chieri / Watanabe, Yoko / Sanoh, Seigo / Nakajima, Hiroyuki / Uramaru, Naoto / Kojima, Hiroyuki / Yoshinari, Kouichi / Ohta, Shigeru / Kitamura, Shigeyuki

Heliyon

2019 Volume 5, Issue 9, Page(s) e02466

Abstract: In this study, we used reporter gene assays in COS-1 cells to examine the activation of rat pregnane X receptor (PXR), rat constitutive androstane receptor (CAR) and rat peroxisome-proliferator activated receptor (PPAR)α by pyrethroid pesticides, and to ... ...

Abstract	In this study, we used reporter gene assays in COS-1 cells to examine the activation of rat pregnane X receptor (PXR), rat constitutive androstane receptor (CAR) and rat peroxisome-proliferator activated receptor (PPAR)α by pyrethroid pesticides, and to understand the effects of metabolic modification on their activities. All eight pyrethroids tested in this study showed rat PXR agonistic activity; deltamethrin was the most potent, followed by
Language	English
Publishing date	2019-09-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2019.e02466
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Article ; Online: Activation of PXR, CAR and PPARα by pyrethroid pesticides and the effect of metabolism by rat liver microsomes

Fujino, Chieri / Watanabe, Yōko / Sanoh, Seigo / Nakajima, Hiroyuki / Uramaru, Naoto / Kojima, Hiroyuki / Yoshinari, Kouichi / Ohta, Shigeru / Kitamura, Shigeyuki

Heliyon. 2019 Sept., v. 5, no. 9 p.e02466-

2019

Abstract	In this study, we used reporter gene assays in COS-1 cells to examine the activation of rat pregnane X receptor (PXR), rat constitutive androstane receptor (CAR) and rat peroxisome-proliferator activated receptor (PPAR)α by pyrethroid pesticides, and to understand the effects of metabolic modification on their activities. All eight pyrethroids tested in this study showed rat PXR agonistic activity; deltamethrin was the most potent, followed by cis-permethrin and cypermethrin. However, when the pyrethroids were incubated with rat liver microsomes, their rat PXR activities were decreased to various extents. Cis- and trans-permethrin showed weak rat CAR agonistic activity, while the other pyrethroids were inactive. However, fenvalerate showed dose-dependent inverse agonistic activity toward rat CAR, and this activity was reduced after metabolism. None of the pyrethroids showed rat PPARα agonistic activity, but a metabolite of cis-/trans-permethrin and phenothrin, 3-phenoxybenzoic acid, activated rat PPARα. Since PXR, CAR and PPARα regulate various xenobiotic/endobiotic-metabolizing enzymes, activation of these receptors by pyrethroids may result in endocrine disruption due to changes of hormone-metabolizing activities.
Keywords	androstanes ; cypermethrin ; deltamethrin ; dose response ; fenvalerate ; liver microsomes ; metabolism ; metabolites ; peroxisome proliferator-activated receptors ; phenothrin ; pregnanes ; pyrethrins ; rats ; reporter genes ; Environmental health ; Environmental science ; Pesticide ; Toxicology ; CAR ; Nuclear receptor activation ; PPARα ; PXR ; Pyrethroid pesticide
Language	English
Dates of publication	2019-09
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	NAL-AP-2-clean ; Use and reproduction
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2019.e02466
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Transesterification of a series of 12 parabens by liver and small-intestinal microsomes of rats and humans.

Fujino, Chieri / Watanabe, Yoko / Uramaru, Naoto / Kitamura, Shigeyuki

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

2014 Volume 64, Page(s) 361–368

Abstract: Hydrolytic transformation of parabens (4-hydroxybenzoic acid esters; used as antibacterial agents) to 4-hydroxybenzoic acid and alcohols by tissue microsomes is well-known both in vitro and in vivo. Here, we investigated transesterification reactions of ... ...

Abstract	Hydrolytic transformation of parabens (4-hydroxybenzoic acid esters; used as antibacterial agents) to 4-hydroxybenzoic acid and alcohols by tissue microsomes is well-known both in vitro and in vivo. Here, we investigated transesterification reactions of parabens catalyzed by rat and human microsomes, using a series of 12 parabens with C1-C12 alcohol side chains. Transesterification of parabens by rat liver and small-intestinal microsomes occurred in the presence of alcohols in the microsomal incubation mixture. Among the 12 parabens, propylparaben was most effectively transesterified by rat liver microsomes with methanol or ethanol, followed by butylparaben. Relatively low activity was observed with longer-side-chain parabens. In contrast, small-intestinal microsomes exhibited higher activity towards moderately long side-chain parabens, and showed the highest activity toward octylparaben. When parabens were incubated with liver or small-intestinal microsomes in the presence of C1-C12 alcohols, ethanol and decanol were most effectively transferred to parabens by rat liver microsomes and small-intestinal microsomes, respectively. Human liver and small-intestinal microsomes also exhibited significant transesterification activities with different substrate specificities, like rat microsomes. Carboxylesterase isoforms, CES1b and CES1c, and CES2, exhibited significant transesterification activity toward parabens, and showed similar substrate specificity to human liver and small-intestinal microsomes, respectively.
MeSH term(s)	Animals ; Esterification ; Humans ; Hydrolysis ; Intestines/metabolism ; Liver/metabolism ; Microsomes/metabolism ; Parabens/metabolism ; Rats
Chemical Substances	Parabens
Language	English
Publishing date	2014-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2013.12.013
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Article ; Online: Activation of PXR, CAR and PPARα by pyrethroid pesticides and the effect of metabolism by rat liver microsomes

Chieri Fujino / Yoko Watanabe / Seigo Sanoh / Hiroyuki Nakajima / Naoto Uramaru / Hiroyuki Kojima / Kouichi Yoshinari / Shigeru Ohta / Shigeyuki Kitamura

Heliyon, Vol 5, Iss 9, Pp e02466- (2019)

2019

Abstract	In this study, we used reporter gene assays in COS-1 cells to examine the activation of rat pregnane X receptor (PXR), rat constitutive androstane receptor (CAR) and rat peroxisome-proliferator activated receptor (PPAR)α by pyrethroid pesticides, and to understand the effects of metabolic modification on their activities. All eight pyrethroids tested in this study showed rat PXR agonistic activity; deltamethrin was the most potent, followed by cis-permethrin and cypermethrin. However, when the pyrethroids were incubated with rat liver microsomes, their rat PXR activities were decreased to various extents. Cis- and trans-permethrin showed weak rat CAR agonistic activity, while the other pyrethroids were inactive. However, fenvalerate showed dose-dependent inverse agonistic activity toward rat CAR, and this activity was reduced after metabolism. None of the pyrethroids showed rat PPARα agonistic activity, but a metabolite of cis-/trans-permethrin and phenothrin, 3-phenoxybenzoic acid, activated rat PPARα. Since PXR, CAR and PPARα regulate various xenobiotic/endobiotic-metabolizing enzymes, activation of these receptors by pyrethroids may result in endocrine disruption due to changes of hormone-metabolizing activities.
Keywords	Environmental health ; Environmental science ; Pesticide ; Toxicology ; CAR ; Liver microsomes ; Science (General) ; Q1-390 ; Social sciences (General) ; H1-99
Subject code	571
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparative study of the effect of 17 parabens on PXR-, CAR- and PPARα-mediated transcriptional activation.

Fujino, Chieri / Watanabe, Yoko / Sanoh, Seigo / Hattori, Shoko / Nakajima, Hiroyuki / Uramaru, Naoto / Kojima, Hiroyuki / Yoshinari, Kouichi / Ohta, Shigeru / Kitamura, Shigeyuki

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

2019 Volume 133, Page(s) 110792

Abstract: Parabens are widely used as preservatives in personal care products, medicines and foods, resulting in substantial human exposures, even though some harmful effects, such as endocrine-disrupting activity, have been reported. Pregnane X receptor (PXR), ... ...

Abstract	Parabens are widely used as preservatives in personal care products, medicines and foods, resulting in substantial human exposures, even though some harmful effects, such as endocrine-disrupting activity, have been reported. Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα), which are members of the nuclear receptor superfamily, regulate the metabolism of endogenous substrates including hormones. Therefore, we hypothesized that parabens may alter hormone-metabolizing activities by acting on these receptors, and such changes could contribute to the endocrine-disrupting activity. To test this idea, we systematically examined the effects of 17 parabens on these receptors using reporter gene assays. Nine parabens significantly activated human and rat PXR. Parabens with C2-C5 (linear and branched) side chains were most active. Butylparaben and isobutylparaben also significantly activated rat CAR. We found that long-side-chain (C7-C12) parabens showed up to 2-fold activation of PPARα at 10 μM. Furthermore, pentylparaben and hexylparaben showed rat PXR antagonistic activity and rat CAR inverse agonistic activity. The activity of butylparaben towards PXR and CAR was lost after carboxylesterase-mediated metabolism. These findings confirm that parabens influence the activities of PXR, CAR and PPARα, and thus have the potential to contribute to endocrine disruption by altering hormone metabolism.
MeSH term(s)	Animals ; Drug Inverse Agonism ; Humans ; Male ; Microsomes, Liver/metabolism ; PPAR alpha/agonists ; PPAR alpha/genetics ; PPAR alpha/metabolism ; Parabens/metabolism ; Parabens/pharmacology ; Pregnane X Receptor/antagonists & inhibitors ; Pregnane X Receptor/genetics ; Pregnane X Receptor/metabolism ; Rats, Sprague-Dawley ; Receptors, Cytoplasmic and Nuclear/agonists ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Transcriptional Activation/drug effects
Chemical Substances	NR1I2 protein, human ; Nr1i2 protein, rat ; PPAR alpha ; Parabens ; Pregnane X Receptor ; Receptors, Cytoplasmic and Nuclear ; constitutive androstane receptor (438XLITDI3)
Language	English
Publishing date	2019-08-28
Publishing country	England
Document type	Journal Article
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2019.110792
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Article: Comparative study of the effect of 17 parabens on PXR-, CAR- and PPARα-mediated transcriptional activation

Fujino, Chieri / Watanabe, Yoko / Sanoh, Seigo / Hattori, Shoko / Nakajima, Hiroyuki / Uramaru, Naoto / Kojima, Hiroyuki / Yoshinari, Kouichi / Ohta, Shigeru / Kitamura, Shigeyuki

Food and chemical toxicology. 2019 Aug. 23,

2019

Abstract	Parabens are widely used as preservatives in personal care products, medicines and foods, resulting in substantial human exposures, even though some harmful effects, such as endocrine-disrupting activity, have been reported. Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα), which are members of the nuclear receptor superfamily, regulate the metabolism of endogenous substrates including hormones. Therefore, we hypothesized that parabens may alter hormone-metabolizing activities by acting on these receptors, and such changes could contribute to the endocrine-disrupting activity. To test this idea, we systematically examined the effects of 17 parabens on these receptors using reporter gene assays. Nine parabens significantly activated human and rat PXR. Parabens with C2–C5 (linear and branched) side chains were most active. Butylparaben and isobutylparaben also significantly activated rat CAR. We found that long-side-chain (C7–C12) parabens showed up to 2-fold activation at 10 μM. Furthermore, pentylparaben and hexylparaben showed rat PXR antagonistic activity and rat CAR inverse agonistic activity. The activity of butylparaben towards PXR and CAR was lost after carboxylesterase-mediated metabolism. These findings confirm that parabens influence the activities of PXR, CAR, and PPARα, and thus have the potential to contribute to endocrine disruption by altering hormone metabolism.
Keywords	androstanes ; comparative study ; exposure assessment ; foods ; hormone metabolism ; hormones ; human cell lines ; peroxisome proliferator-activated receptor alpha ; personal care products ; pregnanes ; preservatives ; rats ; reporter genes ; transcriptional activation
Language	English
Dates of publication	2019-0823
Publishing place	Elsevier Ltd
Document type	Article
Note	Pre-press version
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2019.110792
Database	NAL-Catalogue (AGRICOLA)

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