Premium
Differential expression of cytochrome p450 induced by smokeless tobacco mediates genotoxic damage in rats
Author(s) -
Avti Pramod Kumar,
Arora Surender Kumar,
Pathak Chander Mohan,
Khanduja Krishan Lal
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a670-c
Subject(s) - cyp2e1 , micronucleus test , micronucleus , kidney , pharmacology , dna damage , dna fragmentation , apoptosis , chemistry , genotoxicity , cytochrome p450 , oxidative stress , medicine , toxicity , endocrinology , physiology , biochemistry , programmed cell death , dna , metabolism
The use of smokeless tobacco (ST) is popular in USA, Europe and South East Asian countries. Apart from oral cancer, the molecular mechanisms involved in other ST‐related health effects are unknown. Hence, the effects of chronic use of aqueous extract of ‘gutkha’ (AEGT) on cytochrome p450 (cyp) mediated genotoxic damage in liver, lung, and kidney of male Wistar rats were studied. Materials and Methods: Animal Experiments were conducted after Institutes Animal Ethical Clearance. The lyophilized AEGT was orally administered to animals at a low‐dose (96 mg/kg body weight/day) for 2 and 32 weeks, and at a high‐dose (960 mg/kg body weight/day) for 2 weeks. The immunohistochemical expression of cyp1A1, 1A2, 2E1 and GST‐μ; myeloperoxidase (MPO) and caspase‐3 activity and DNA fragmentation in above organs and plasma TNF‐α, protein carbonyls and blood micronuclei formation were measured. Results: Low‐dose of AEGT administration for 32 weeks differentially expressed the lung, liver and kidney cyp1A1, 1A2, 2E1 and GST‐μ. There was significant increase (p<0.05) in MPO, caspase‐3 activity and DNA fragmentation. The extent of this increase was less due to high‐dose of AEGT for 2 weeks. High‐dose and low‐dose AEGT for 2 and 32 weeks significantly enhanced plasma TNF‐α by 7% and 23%, protein carbonyls by 4% and 12% respectively. Micronuclei formation in whole blood was increased by 14% in long term group. Conclusion: Chronic use of AEGT induces cytochrome p450's, which mediates genotoxic damage in various organs of rats. The differential damage by AEGT may be due to variable sensitivities and functions carried out by these organs. These changes may be responsible for AEGT‐induced pathogenesis. Supported by PGIMER, Chandigarh, India.