Metabolism of the c-Fos/Activator Protein-1 Inhibitor T-5224 by Multiple Human UDP-Glucuronosyltransferase Isoforms

Uchihashi, Shinsuke; Fukumoto, Hiroyuki; Onoda, Makoto; Hayakawa, Hiroyoshi; Ikushiro, Shinichi; Sakaki, Toshiyuki

doi:10.1124/dmd.110.037952

Cited by 23 publications

(22 citation statements)

References 35 publications

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“…UGT1A4 and ABCG8 proteins were reported to be expressed in human liver (Klett et al, 2004;Izukawa et al, 2009;Uchihashi et al, 2011). However, these molecules were not quantifiable in the present study (Tables 2 and 5).…”

Section: Ohtsuki Et Alcontrasting

confidence: 51%

Simultaneous Absolute Protein Quantification of Transporters, Cytochromes P450, and UDP-Glucuronosyltransferases as a Novel Approach for the Characterization of Individual Human Liver: Comparison with mRNA Levels and Activities

et al. 2011

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ABSTRACT:The purpose of the present study was to determine the absolute protein expression levels of multiple drug-metabolizing enzymes and transporters in 17 human liver biopsies, and to compare them with the mRNA expression levels and functional activities to evaluate the suitability of the three measures as parameters of hepatic metabolism. Absolute protein expression levels of 13 cytochrome P450 (P450) enzymes, NADPH-P450 reductase (P450R) and 6 UDPglucuronosyltransferase (UGT) enzymes in microsomal fraction, and 22 transporters in plasma membrane fraction were determined using liquid chromatography/tandem mass spectrometry. CYP2C9, CYP2E1, CYP3A4, CYP2A6, UGT1A6, UGT2B7, UGT2B15, and P450R were abundantly expressed (more than 50 pmol/mg protein) in human liver microsomes. The protein expression levels of CYP3A4, CYP2B6, and CYP2C8 were each highly correlated with the corresponding enzyme activity and mRNA expression levels, whereas for other P450s, the protein expression levels were better correlated with the enzyme activities than the mRNA expression levels were. Among transporters, the protein expression level of organic anion-transporting polypeptide 1B1 was relatively highly correlated with the mRNA expression level. However, other transporters showed almost no correlation. These findings indicate that protein expression levels determined by the present simultaneous quantification method are a useful parameter to assess differences of hepatic function between individuals.

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Section: Ohtsuki Et Alcontrasting

confidence: 51%

Simultaneous Absolute Protein Quantification of Transporters, Cytochromes P450, and UDP-Glucuronosyltransferases as a Novel Approach for the Characterization of Individual Human Liver: Comparison with mRNA Levels and Activities

et al. 2011

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“…The V max /K m of UGT2B7 was 3.4 times higher than that of UGT2B17, whereas both K m values were almost identical (Table 3). Because the levels of UGT2B7 and UGT2B17 in the recombinant microsomes were similar (0.6 -0.8 nmol/mg protein) as described in our previous report (Uchihashi et al, 2011), the enzymatic activity of UGT2B7 appears to be significantly higher than that of UGT2B17. In addition, UGT2B7 mRNA is higher than UGT2B17 mRNA in the human liver (Congiu et al, 2002;Court, 2005;Izukawa et al, 2009).…”

Section: Metabolism Of Sesamin In Human Livermentioning

confidence: 92%

Sequential Metabolism of Sesamin by Cytochrome P450 and UDP-Glucuronosyltransferase in Human Liver

et al. 2011

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ABSTRACT:Our previous study revealed that CYP2C9 played a central role in sesamin monocatecholization. In this study, we focused on the metabolism of sesamin monocatechol that was further converted into the dicatechol form by cytochrome P450 (P450) or the glucuronide by UDP-glucuronosyltransferase (UGT). Catecholization of sesamin monocatechol enhances its antioxidant activity, whereas glucuronidation strongly reduces its antioxidant activity. In human liver microsomes, the glucuronidation activity was much higher than the catecholization activity toward sesamin monocatechol. In contrast, in rat liver microsomes, catecholization is predominant over glucuronidation. In addition, rat liver produced two isomers of the glucuronide, whereas human liver produced only one glucuronide. These results suggest a significant species-based difference in the metabolism of sesamin between humans and rats. Kinetic studies using recombinant human UGT isoforms identified UGT2B7 as the most important UGT isoform for glucuronidation of sesamin monocatechol. In addition, a good correlation was observed between the glucuronidation activity and UGT2B7-specific activity in in vitro studies using 10 individual human liver microsomes. These results strongly suggest that UGT2B7 plays an important role in glucuronidation of sesamin monocatechol. Interindividual difference among the 10 human liver microsomes is approximately 2-fold. These results, together with our previous results on the metabolism of sesamin by human P450, suggest a small interindividual difference in sesamin metabolism. We observed the methylation activity toward sesamin monocatechol by catechol O-methyl transferase (COMT) in human liver cytosol. On the basis of these results, we concluded that CYP2C9, UGT2B7, and COMT played essential roles in the metabolism of sesamin in the human liver.

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“…By use of human liver microsomes (HLMs), human intestinal microsomes (HIMs), recombinant human cytochrome P450 (CYP450), and UDP-glucuronosyltransferases (UGTs) isoforms expressed in baculovirus-infected insect cells, it was predicted that 51 was converted to its acyl O -glucuronide by UGT1A1 and UGT1A3 and to its hydroxyl O -glucuronide by several UGTs, but it was not metabolized by the P450. 5 Moreover, the glucuronidation of 51 was estimated to predominantly occur in the liver by comparing the intrinsic clearances (CL int ) between HLM and HIM.…”

Section: Development Of Small Molecules Targeting Ap-1mentioning

confidence: 99%

Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1)

et al. 2014

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Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation. Accumulating evidence supports that AP-1 plays an important role in several severe disorders including cancer, fibrosis, and organ injury, as well as inflammatory disorders such as asthma, psoriasis, and rheumatoid arthritis. AP-1 has emerged as an actively pursued drug discovery target over the past decade. Excitingly, a selective AP-1 inhibitor T-5224 (51) has been investigated in phase II human clinical trials. Nevertheless, no effective AP-1 inhibitors have yet been approved for clinical use. Despite significant advances achieved in understanding AP-1 biology and function, as well as the identification of small molecules modulating AP-1 associated signaling pathways, medicinal chemistry efforts remain an urgent need to yield selective and efficacious AP-1 inhibitors as a viable therapeutic strategy for human diseases.

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Metabolism of the c-Fos/Activator Protein-1 Inhibitor T-5224 by Multiple Human UDP-Glucuronosyltransferase Isoforms

Cited by 23 publications

References 35 publications

Simultaneous Absolute Protein Quantification of Transporters, Cytochromes P450, and UDP-Glucuronosyltransferases as a Novel Approach for the Characterization of Individual Human Liver: Comparison with mRNA Levels and Activities

Simultaneous Absolute Protein Quantification of Transporters, Cytochromes P450, and UDP-Glucuronosyltransferases as a Novel Approach for the Characterization of Individual Human Liver: Comparison with mRNA Levels and Activities

Sequential Metabolism of Sesamin by Cytochrome P450 and UDP-Glucuronosyltransferase in Human Liver

Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1)

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