Tolfenamic acid suppresses cytochrome P450 2E1 expression in mouse liver

Shadab A. Siddiqi, Mohammed I. Shukoor, Samata Tiwari, Umesh Tanaji Sankpal, Pius Maliakal, Sarah F. Connelly, Shaila Siddiqi, Riyaz Mahammad Basha

Research output: Contribution to journalArticle

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Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) play a significant role in the chemoprevention of cancer. We recently showed the chemopreventive response of a NSAID, 2-[(3-chloro-2-methylphenyl)amino]benzoic acid) known as tolfenamic acid (TA) in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in rats. Pre-clinical studies showed that TA inhibits Specificity protein (Sp) transcription factors and acts as an anti-cancer agent in several cancer models; however the pertinent mechanisms associated with its chemopreventive response in esophageal cancer are not known. Since the bioactivation of carcinogens through cytochrome P450 (CYP) is critical for the induction of cancer, we have studied the effect of TA on critical CYP isozymes in mouse liver samples. Athymic nude mice were treated with vehicle (corn oil) or TA (50 mg kg -1, 3 times per week) for 4 weeks. Protein extracts (whole cell lysates and microsomal fractions) were prepared from liver tissue and the expression of various CYP isozymes was determined by Western blot analysis. Rat (Sprague-Dawley) livers were harvested and primary hepatocyte cultures were treated with vehicle (DMSO) or TA (50 μM) and cell viability was assessed at 2 and 5 days post-treatment. TA caused remarkable decrease in the expression of CYP2E1 in both liver lysates and sub-cellular fraction, while its response on other tested isozymes was marginal. TA did not affect the body weight of animals (mice) and viability of rat hepatocytes. These results demonstrate that TA modulates the expression of CYP2E1 which is associated with the bioactivation of carcinogens without causing apparent toxicity. These data suggest that TA-induced inhibition of CYP2E1 attenuates the bioactivation of carcinogens potentially leading to the chemoprevention of NMBA-induced esophageal tumorigenesis in rats.

Original languageEnglish
Pages (from-to)1122-1129
Number of pages8
JournalIntegrative Biology (United Kingdom)
Volume4
Issue number9
DOIs
StatePublished - 1 Jan 2012

Fingerprint

Cytochrome P-450 CYP2E1
Liver
Rats
Carcinogens
Cytochrome P-450 Enzyme System
Isoenzymes
nitrosobenzylmethylamine
Chemoprevention
Neoplasms
Nude Mice
Hepatocytes
Sp Transcription Factors
Anti-Inflammatory Agents
tolfenamic acid
Benzoic Acid
Corn Oil
Esophageal Neoplasms
Dimethyl Sulfoxide
Cell Extracts
Pharmaceutical Preparations

Cite this

Siddiqi, Shadab A. ; Shukoor, Mohammed I. ; Tiwari, Samata ; Sankpal, Umesh Tanaji ; Maliakal, Pius ; Connelly, Sarah F. ; Siddiqi, Shaila ; Basha, Riyaz Mahammad. / Tolfenamic acid suppresses cytochrome P450 2E1 expression in mouse liver. In: Integrative Biology (United Kingdom). 2012 ; Vol. 4, No. 9. pp. 1122-1129.
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title = "Tolfenamic acid suppresses cytochrome P450 2E1 expression in mouse liver",
abstract = "Non-steroidal anti-inflammatory drugs (NSAIDs) play a significant role in the chemoprevention of cancer. We recently showed the chemopreventive response of a NSAID, 2-[(3-chloro-2-methylphenyl)amino]benzoic acid) known as tolfenamic acid (TA) in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in rats. Pre-clinical studies showed that TA inhibits Specificity protein (Sp) transcription factors and acts as an anti-cancer agent in several cancer models; however the pertinent mechanisms associated with its chemopreventive response in esophageal cancer are not known. Since the bioactivation of carcinogens through cytochrome P450 (CYP) is critical for the induction of cancer, we have studied the effect of TA on critical CYP isozymes in mouse liver samples. Athymic nude mice were treated with vehicle (corn oil) or TA (50 mg kg -1, 3 times per week) for 4 weeks. Protein extracts (whole cell lysates and microsomal fractions) were prepared from liver tissue and the expression of various CYP isozymes was determined by Western blot analysis. Rat (Sprague-Dawley) livers were harvested and primary hepatocyte cultures were treated with vehicle (DMSO) or TA (50 μM) and cell viability was assessed at 2 and 5 days post-treatment. TA caused remarkable decrease in the expression of CYP2E1 in both liver lysates and sub-cellular fraction, while its response on other tested isozymes was marginal. TA did not affect the body weight of animals (mice) and viability of rat hepatocytes. These results demonstrate that TA modulates the expression of CYP2E1 which is associated with the bioactivation of carcinogens without causing apparent toxicity. These data suggest that TA-induced inhibition of CYP2E1 attenuates the bioactivation of carcinogens potentially leading to the chemoprevention of NMBA-induced esophageal tumorigenesis in rats.",
author = "Siddiqi, {Shadab A.} and Shukoor, {Mohammed I.} and Samata Tiwari and Sankpal, {Umesh Tanaji} and Pius Maliakal and Connelly, {Sarah F.} and Shaila Siddiqi and Basha, {Riyaz Mahammad}",
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Siddiqi, SA, Shukoor, MI, Tiwari, S, Sankpal, UT, Maliakal, P, Connelly, SF, Siddiqi, S & Basha, RM 2012, 'Tolfenamic acid suppresses cytochrome P450 2E1 expression in mouse liver', Integrative Biology (United Kingdom), vol. 4, no. 9, pp. 1122-1129. https://doi.org/10.1039/c2ib20127e

Tolfenamic acid suppresses cytochrome P450 2E1 expression in mouse liver. / Siddiqi, Shadab A.; Shukoor, Mohammed I.; Tiwari, Samata; Sankpal, Umesh Tanaji; Maliakal, Pius; Connelly, Sarah F.; Siddiqi, Shaila; Basha, Riyaz Mahammad.

In: Integrative Biology (United Kingdom), Vol. 4, No. 9, 01.01.2012, p. 1122-1129.

Research output: Contribution to journalArticle

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T1 - Tolfenamic acid suppresses cytochrome P450 2E1 expression in mouse liver

AU - Siddiqi, Shadab A.

AU - Shukoor, Mohammed I.

AU - Tiwari, Samata

AU - Sankpal, Umesh Tanaji

AU - Maliakal, Pius

AU - Connelly, Sarah F.

AU - Siddiqi, Shaila

AU - Basha, Riyaz Mahammad

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N2 - Non-steroidal anti-inflammatory drugs (NSAIDs) play a significant role in the chemoprevention of cancer. We recently showed the chemopreventive response of a NSAID, 2-[(3-chloro-2-methylphenyl)amino]benzoic acid) known as tolfenamic acid (TA) in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in rats. Pre-clinical studies showed that TA inhibits Specificity protein (Sp) transcription factors and acts as an anti-cancer agent in several cancer models; however the pertinent mechanisms associated with its chemopreventive response in esophageal cancer are not known. Since the bioactivation of carcinogens through cytochrome P450 (CYP) is critical for the induction of cancer, we have studied the effect of TA on critical CYP isozymes in mouse liver samples. Athymic nude mice were treated with vehicle (corn oil) or TA (50 mg kg -1, 3 times per week) for 4 weeks. Protein extracts (whole cell lysates and microsomal fractions) were prepared from liver tissue and the expression of various CYP isozymes was determined by Western blot analysis. Rat (Sprague-Dawley) livers were harvested and primary hepatocyte cultures were treated with vehicle (DMSO) or TA (50 μM) and cell viability was assessed at 2 and 5 days post-treatment. TA caused remarkable decrease in the expression of CYP2E1 in both liver lysates and sub-cellular fraction, while its response on other tested isozymes was marginal. TA did not affect the body weight of animals (mice) and viability of rat hepatocytes. These results demonstrate that TA modulates the expression of CYP2E1 which is associated with the bioactivation of carcinogens without causing apparent toxicity. These data suggest that TA-induced inhibition of CYP2E1 attenuates the bioactivation of carcinogens potentially leading to the chemoprevention of NMBA-induced esophageal tumorigenesis in rats.

AB - Non-steroidal anti-inflammatory drugs (NSAIDs) play a significant role in the chemoprevention of cancer. We recently showed the chemopreventive response of a NSAID, 2-[(3-chloro-2-methylphenyl)amino]benzoic acid) known as tolfenamic acid (TA) in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in rats. Pre-clinical studies showed that TA inhibits Specificity protein (Sp) transcription factors and acts as an anti-cancer agent in several cancer models; however the pertinent mechanisms associated with its chemopreventive response in esophageal cancer are not known. Since the bioactivation of carcinogens through cytochrome P450 (CYP) is critical for the induction of cancer, we have studied the effect of TA on critical CYP isozymes in mouse liver samples. Athymic nude mice were treated with vehicle (corn oil) or TA (50 mg kg -1, 3 times per week) for 4 weeks. Protein extracts (whole cell lysates and microsomal fractions) were prepared from liver tissue and the expression of various CYP isozymes was determined by Western blot analysis. Rat (Sprague-Dawley) livers were harvested and primary hepatocyte cultures were treated with vehicle (DMSO) or TA (50 μM) and cell viability was assessed at 2 and 5 days post-treatment. TA caused remarkable decrease in the expression of CYP2E1 in both liver lysates and sub-cellular fraction, while its response on other tested isozymes was marginal. TA did not affect the body weight of animals (mice) and viability of rat hepatocytes. These results demonstrate that TA modulates the expression of CYP2E1 which is associated with the bioactivation of carcinogens without causing apparent toxicity. These data suggest that TA-induced inhibition of CYP2E1 attenuates the bioactivation of carcinogens potentially leading to the chemoprevention of NMBA-induced esophageal tumorigenesis in rats.

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