CYP2A13 expressed in human bladder metabolically activates 4‐aminobiphenyl

Nakajima, Miki; Itoh, Masahiro; Sakai, Haruko; Fukami, Tatsuki; Katoh, Miki; Yamazaki, Hiroshi; Kadlubar, Fred F.; Imaoka, Shingi; Funae, Yoshihiko; Yokoi, Tsuyoshi

doi:10.1002/ijc.22136

Cited by 59 publications

(69 citation statements)

References 34 publications

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“…Total RNA was isolated from human hepatocytes or mouse liver using RNAiso (Takara) following the manufacturer's protocol, and cDNA was synthesized as described previously [15]. The primers for human CYP2A6 [15] and human GAPDH [16] were described previously.…”

Section: Real-time Rt-pcr Analysesmentioning

confidence: 99%

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Human CYP2A6 is regulated by nuclear factor-erythroid 2 related factor 2

Yokota

Higashi

Fukami

et al. 2011

Biochemical Pharmacology

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Human CYP2A6 is responsible for the metabolism of nicotine and coumarin as well as the metabolic activation of tobacco-related nitrosamines. Earlier studies revealed that CYP2A6 activity was increased by dietary cadmium or cruciferous vegetables, but the underlying mechanisms remain to be clarified. In the present study, we investigated the possibility that Nrf2 might be involved in the regulation of CYP2A6. Real-time RT-PCR analysis revealed that the CYP2A6 mRNA level in human hepatocytes was significantly (P < 0.01, 1.4 fold) induced by 10 µM sulforaphane (SFN), a typical activator of Nrf2. A computer-based search identified three putative antioxidant response elements (AREs) in the 5'-flanking region of the CYP2A6 gene at positions -1212, -2444, and -3441, termed ARE1, ARE2, and ARE3, respectively. Electrophoretic mobility shift assays demonstrated that Nrf2 bound only to ARE1. Luciferase assays using HepG2 cells revealed that the overexpression of Nrf2 significantly increased the reporter activities of the constructs containing a 30-bp fragment that included ARE1. However, the activity of the construct containing the intact 5'-flanking region (-1 to -1395) including ARE1 was not increased by the overexpression of Nrf2. In contrast, when the reporter construct was injected into mice via the tail vein, the reporter activity in the liver was significantly (P < 0.05, 1.9 fold) increased by SFN (1 mg/head) administration. In conclusion, we found that human CYP2A6 is regulated via Nrf2, suggesting that CYP2A6 is induced under oxidative stress.

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Section: Real-time Rt-pcr Analysesmentioning

confidence: 99%

“…The primers for human CYP2A6 [15] and human GAPDH [16] were described previously. The forward and reverse primers for mouse NAD(P)H:quinone oxidoreductase 1 (NQO1) were 5'-CCCTGATTGTACTGGCCCATT-3' and 5'-CGTCCTTCCTTATATGCTAG-3', respectively.…”

Section: Real-time Rt-pcr Analysesmentioning

confidence: 99%

Human CYP2A6 is regulated by nuclear factor-erythroid 2 related factor 2

Yokota

Higashi

Fukami

et al. 2011

Biochemical Pharmacology

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“…CYP2A6 hepatic over expression is elevated in hepatocellular carcinoma associated with cirrhosis and chronic inflammation [10]. Inhibition of CYP2A by chalepensin causes cytotoxicity in carcinoma cell lines and this might have significance in target organs expressing CYP2A6, like testis, ovary, uterus and liver [11].…”

Section: Introductionmentioning

confidence: 99%

A Thiazole Analogue Exhibits an Anti-Proliferative Effect in Different Human Carcinoma Cell Lines and Its Mechanism Based on Molecular Modeling

Amin¹,

El-Araby²,

Eid³

et al. 2017

ABC

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Purpose: Aim of this study is to assess the anti-proliferative effect of the thiazole analogue (5-acetyl-4-methyl-2-(3-pyridyl) thiazole) with different human carcinoma cell lines and to postulate its possible mechanism of action using molecular modeling. Methods: Three different human carcinoma cell lines were used namely hepatocyte carcinoma (HEPG2), breast adenocarcinoma (MCF7) and colon cancer (HCT116). Molecular docking simulations for tested thiazole analogue and its virtual analogues against the cytochrome P-450 2A6 enzyme and mutated SOD were performed. Results: Cell lines cytotoxicity revealed that the tested thiazole analogue exerts a significant anti-proliferative activity in all the used human carcinoma cell lines with a pronounced anti-proliferative effect in liver carcinoma cell line HEPG2 (IC 50 = 23.8 µg/ml) whereas the anti-proliferative effect in colon carcinoma and breast cancer cell lines was poor with IC 50 = 50 µg/ml and IC 50 > 50 µg/ml respectively. The postulated mechanism of action revealed the high affinity to inhibit SOD and CYP2A6 enzymes in the liver. Conclusion: The thiazole analogue (5-acetyl-4-methyl-2-(3-pyridyl)thiazole) is a potential liver specific anticancer agent capable of interfering with both apoptotic signaling pathway and the free radical processing in liver which leads to more studies on liver cancer from different perspective rather than the apoptotic signaling pathway.

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“…Our previous studies demonstrated that CYP2A13 is the most efficient human P450 enzyme for the metabolic activation of NNK, a tobacco-specific toxicant and suspected human carcinogen (Su et al, 2000). CYP2A13 can also metabolically activate 4-aminobiphenyl, another carcinogen in cigarette smoke (Nakajima et al, 2006). In addition, CYP2A13 is highly efficient in metabolizing nicotine (Bao et al, 2005) as well as the metabolic activation of aflatoxin B 1 , naphthalene, and styrene (Fukami et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Selective Expression of CYP2A13 in Human Pancreatic α-Islet Cells

Guo

Zhu²,

Lǚ³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Exposure to cigarette smoke is an etiological factor of human pancreatic cancer and has been associated with an increased risk of pancreatic diseases, including pancreatitis and diabetes. The toxicants in cigarette smoke can reach pancreatic tissue, and most of the toxicants require cytochrome P450 (P450)-mediated metabolic activation to exert their toxicity. Among all the human P450 enzymes, CYP2A13 is the most efficient enzyme in the metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major tobacco-specific toxicant and a suspected human carcinogen. It also metabolically activates 4-aminobiphenyl, another toxicant in cigarette smoke. Immunohistochemical analysis in this study demonstrated that CYP2A13 was selectively expressed in the islets but not in the exocrine portion of adult human pancreas. Further study using dual immunofluorescence labeling technique showed that CYP2A13 protein was mainly expressed in the ␣-islet but not in ␤-islet cells. The selective expression of CYP2A13 in human pancreatic ␣-islet cells suggests that these islet cells could be damaged by the toxicants existing in cigarette smoke through CYP2A13-mediated in situ metabolic activation. Our result provides a mechanistic insight for human pancreatic diseases that have been associated with cigarette smoke exposure.

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CYP2A13 expressed in human bladder metabolically activates 4‐aminobiphenyl

Cited by 59 publications

References 34 publications

Human CYP2A6 is regulated by nuclear factor-erythroid 2 related factor 2

Human CYP2A6 is regulated by nuclear factor-erythroid 2 related factor 2

A Thiazole Analogue Exhibits an Anti-Proliferative Effect in Different Human Carcinoma Cell Lines and Its Mechanism Based on Molecular Modeling

Selective Expression of CYP2A13 in Human Pancreatic α-Islet Cells

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