Inhibition of human cytochromes P450 2A6 and 2A13 by flavonoids, acetylenic thiophenes and sesquiterpene lactones from  Pluchea indica  and  Vernonia cinerea

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Abstract

The human liver cytochrome P450 (CYP) 2A6 and the respiratory CYP2A13 enzymes play role in nicotine metabolism and activation of tobacco-specific nitrosamine carcinogens. Inhibition of both enzymes could offer a strategy for smoking abstinence and decreased risks of respiratory diseases and lung cancer. In this study, activity-guided isolation identified four flavonoids 1– 4 (apigenin, luteolin, chrysoeriol, quercetin) from Vernonia cinerea and Pluchea indica, four hirsutinolide-type sesquiterpene lactones 5– 8 from V. cinerea, and acetylenic thiophenes 9– 11 from P. indica that inhibited CYP2A6- and CYP2A13-mediated coumarin 7-hydroxylation. Flavonoids were most effective in inhibition against CYP2A6 and CYP2A13, followed by thiophenes, and hirsutinolides. Hirsutinolides and thiophenes exhibited mechanism-based inhibition and in irreversible mode against both enzymes. The inactivation kinetic K _I values of hirsutinolides against CYP2A6 and CYP2A13 were 5.32–15.4 and 0.92–8.67 µM, respectively, while those of thiophenes were 0.11–1.01 and 0.67–0.97 µM, respectively.

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Most cited references 26

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Bioactivation potential of thiophene-containing drugs.

Lucija Peterlin Mašič, Darja Gramec, Marija Sollner Dolenc (2014)

Thiophene is a five-membered, sulfur-containing heteroaromatic ring commonly used as a building block in drugs. It is considered to be a structural alert, as its metabolism can lead to the formation of reactive metabolites. Thiophene S-oxides and thiophene epoxides are highly reactive electrophilic thiophene metabolites whose formation is cytochrome P450-dependent. These reactive thiophene-based metabolites are quite often responsible for drug-induced hepatotoxicity. Tienilic acid is an example of a thiophene-based drug that was withdrawn from the market after only a few months of use, due to severe cases of immune hepatitis. However, inclusion of the thiophene moiety in drugs does not necessarily result in toxic effects. The presence of other, less toxic metabolic pathways, as well as an effective detoxification system in our body, protects us from the bioactivation potential of the thiophene ring. Thus, the presence of a structural alert itself is insufficient to predict a compound's toxicity. The question therefore arises as to which factors significantly influence the toxicity of thiophene-containing drugs. There is no easy way to answer this question. However, the findings presented here indicate that, for a number of reasons, daily dose and alternative metabolic pathways are important factors when predicting toxicity and will therefore be discussed together with examples.

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Exposure and Metabolic Activation Biomarkers of Carcinogenic Tobacco-Specific Nitrosamines.

Stephen S. Hecht, Irina Stepanov, Steven Carmella (2016)

Lung cancer is the leading cause of cancer death in the world, and cigarette smoking is its main cause. Oral cavity cancer is another debilitating and often fatal cancer closely linked to tobacco product use. While great strides have been made in decreasing tobacco use in the United States and some other countries, there are still an estimated 1 billion men and 250 million women in the world who are cigarette smokers and there are hundreds of millions of smokeless tobacco users, all at risk for cancer. Worldwide, lung cancer kills about three people per minute. This Account focuses on metabolites and biomarkers of two powerful tobacco-specific nitrosamine carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), considered to be among the main causes of lung cancer and oral cavity cancer in people who use tobacco products. Three properties of NNK and NNN are critical for successful biomarker studies: they are present in all tobacco products, they are tobacco-specific and are not found in any other product, and they are strong carcinogens. NNK and NNN are converted in humans to urinary metabolites that can be quantified by mass spectrometry as biomarkers of exposure to these carcinogens. They are also metabolized to diazonium ions and related electrophiles that react with DNA to form addition products that can be detected and quantified by mass spectrometry. These urinary metabolites and DNA addition products can serve as biomarkers of exposure and metabolic activation, respectively. The biomarkers of exposure, in particular the urinary NNK metabolites 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, have been extensively applied to document tobacco-specific lung carcinogen uptake in smokers and nonsmokers exposed to secondhand tobacco smoke. Highly sensitive mass spectrometric methods have been developed for quantitative analysis of these NNK metabolites as well as metabolites of NNN in human urine, blood, and toenails. Urinary and serum NNAL have been related to lung cancer risk, and urinary NNN has been related to esophageal cancer risk in prospective epidemiology studies. These results are consistent with carcinogenicity studies of NNK, NNAL, and NNN in rats, which show that NNK and NNAL induce mainly lung tumors, while NNN causes tumors of the esophagus and oral cavity. Biomarkers of metabolic activation of NNK and NNN applied in human studies include the metabolism of deuterium labeled substrates to distinguish NNK and NNN metabolism from that of nicotine and the determination of DNA and hemoglobin adducts in tissues, blood, and oral cells from people exposed to tobacco products. As these methods are continually improved in parallel with the ever increasing sensitivity and selectivity of mass spectrometers, development of a comprehensive biomarker panel for identifying tobacco users at high risk for cancer appears to be a realistic goal. Targeting high risk individuals for smoking cessation and cancer surveillance can potentially decrease the risk of developing fatal cancers.

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Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

Q. M. Zhang, X. Ding, T. Su … (2000)

The human CYP2A subfamily comprises three genes, CYP2A6, CYP2A7, and CYP2A13. CYP2A6 is active toward many carcinogens and is the major coumarin 7-hydroxylase and nicotine C-oxidase in the liver, whereas CYP2A7 is not functional. The function of CYP2A13 has not been characterized. In this study, a CYP2A13 cDNA was prepared by RNA-PCR from human nasal mucosa and was translated using a baculovirus expression system. In a reconstituted system, the expressed CYP2A13 was more active than CYP2A6 in the metabolic activation of hexamethylphosphoramide, N,N-dimethylaniline, 2'-methoxyacetophenone, and N-nitrosomethylphenylamine but was much less active than CYP2A6 in coumarin 7-hydroxylation. Of particular interest, CYP2A13 was highly active in the metabolic activation of a major tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, with a catalytic efficiency much greater than that of other human cytochrome P450 isoforms examined previously. The tissue distribution of CYP2A13 was determined with isoform-specific RNA-PCR. CYP2A13 mRNA was detected in liver and a number of extrahepatic tissues, including nasal mucosa, lung, trachea, brain, mammary gland, prostate, testis, and uterus, but not in heart, kidney, bone marrow, colon, small intestine, spleen, stomach, thymus, or skeletal muscle. Quantitative PCR analysis further revealed that CYP2A13 mRNA is expressed at the highest level in the nasal mucosa, followed by the lung and the trachea. Together, these findings suggest that CYP2A13 plays important roles in xenobiotic toxicity and tobacco-related tumorigenesis in the human respiratory tract.

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Author and article information

Journal

Journal ID (nlm-ta): J Enzyme Inhib Med Chem

Journal ID (iso-abbrev): J Enzyme Inhib Med Chem

Journal ID (publisher-id): IENZ

Journal ID (publisher-id): ienz20

Title: Journal of Enzyme Inhibition and Medicinal Chemistry

Publisher: Taylor & Francis

ISSN (Print): 1475-6366

ISSN (Electronic): 1475-6374

Publication date Collection: 2017

Publication date (Electronic): 31 August 2017

Volume: 32

Issue: 1

Pages: 1136-1142

Affiliations

[a ]Bioengineering Program, Faculty of Engineering, Burapha University , Muang, Chonburi, Thailand;

[b ]Department of Biochemistry, Faculty of Science, Mahidol University , Ratchathewi, Bangkok, Thailand;

[c ]Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University , Muang, Chonburi, Thailand;

[d ]Department of Biochemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University , Muang, Chonburi, Thailand

Author notes

[*]

These authors contributed equally to this work.

Supplemental data for this article can be accessed at https://doi.org/10.6084/m9.figshare.5314423.v1.

CONTACT Songklod Sarapusit songklod@ 123456go.buu.ac.th Department of Biochemistry, Faculty of Science, Burapha University , 169 Long-Hard Bangsaen Rd., Muang, Chonburi20131, Thailand

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Songklod Sarapusit http://orcid.org/0000-0001-6850-3198

Article

Publisher ID: 1363741

DOI: 10.1080/14756366.2017.1363741

PMC ID: 6009911

PubMed ID: 28856944

SO-VID: 27604146-98d3-4b2c-9d83-28c1f8699b62

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 18 May 2017

Date revision received : 28 July 2017

Date accepted : 01 August 2017

Page count

Pages: 7, Words: 5200

Funding

Funded by: Thailand Research Fund 10.13039/501100004396

Award ID: TRG 5780056

Funded by: Burapha University 10.13039/501100006749

Award ID: 86/2559

Funded by: Mahidol University 10.13039/501100004156

Funded by: Burapha University

Award ID: 86/2559

Funded by: Central Instrument Facility, Research Division, Faculty of Science, Mahidol University

Award ID: CIF58/025

Funded by: Thailand Research Fund

Award ID: TRG 5780056

This work was supported by Thailand Research Fund [grant number TRG 5780056]; Burapha University [grant number 86/2559] and Faculty of Science, Mahidol University [grant number CIF58/025 and CIF59/020].

Inhibition of human cytochromes P450 2A6 and 2A13 by flavonoids, acetylenic thiophenes and sesquiterpene lactones from Pluchea indica and Vernonia cinerea

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Most cited references 26

Bioactivation potential of thiophene-containing drugs.

Exposure and Metabolic Activation Biomarkers of Carcinogenic Tobacco-Specific Nitrosamines.

Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

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