Journal of Chemical and Pharmaceutical Research (ISSN : 0975-7384)

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Original Articles: 2011 Vol: 3 Issue: 1

Elucidation and Validation of Metabolic Activation of Human Mammary Carcinogen Dibenzo[a,l] pyrene and its Metabolites Using In silico Approach


The routine testing of any carcinogen are generally performed in the cell free, cell culture and animal models, however, due to involvement of specific isozymes of metabolic activation and detoxification enzymes, these tests become extremely time consuming and expensive in testing metabolic activity of any carcinogens or drugs. The emergence of the In silico approach offers easier, quick, relatively inexpensive and authentic tools to predict potent analogs of a compound, however, it needs validation of the wet lab elucidated specific pathways for activation and detoxification. Dibenzo [a, l] pyrene (DBP), the most potent human carcinogen requires metabolic activation to its reactive diol-epoxides by cytochrome P450 (CYP) isozymes and epoxide hydrolase. The present study tested interactions of DBP, DBP-11, 12-diol (DBPD) with various isozymes of CYP in order to elucidate and validate the wet lab findings using the simple In silico approach. The CYP1A1, 1B1, 2C9 and 2B6 reported in wet lab studies to actively metabolize DBP which also showed strong binding energies (Kcal/mol) of - 11.50, -10.67, -10.37 and -9.76, respectively with inhibition constants ranging between 0.005-0.070 μM. The CYP3A4 showed less binding energy (-9.51 Kcal/mole) which is in alignment with the wet lab reports. Further, better affinity of CYP1A1 and CYP1B1 with the DBPD might be indicative of their involvement in its subsequent conversion to DBPDE. Our results for the first time has In silico validated the metabolic pathways of DBP reported in the wet lab studies and provides a novel platform to study and elucidate the metabolic pathways and mechanism(s) of carcinogens, pharmaceutical drugs and xenobiotics in quick, reliable and economic manner.

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