Title:Murburn Precepts for Cytochrome P450 Mediated Drug/Xenobiotic Metabolism and Homeostasis
Volume: 22
Issue: 4
Author(s): Abhinav Parashar*Kelath M. Manoj*
Affiliation:
- Satyamjayatu: The Science & Ethics Foundation, Snehatheeram, Kulappully, Shoranur-2 (PO), Kerala-679122,India
- Satyamjayatu: The Science & Ethics Foundation, Snehatheeram, Kulappully, Shoranur-2 (PO), Kerala-679122,India
Keywords:
Cytochrome P450 (CYP), murburn concept, drug/xenobiotic metabolism, pharmacokinetics, diffusible reactive oxygen species
(DROS), CYP3A4.
Abstract: Aims: We aim to demonstrate why deeming diffusible reactive oxygen species (DROS) as toxic
wastes do not afford a comprehensive understanding of cytochrome P450 mediated microsomal xenobiotic
metabolism (mXM).
Background: Current pharmacokinetic investigations consider reactive oxygen species formed in microsomal
reactions as toxic waste products, whereas our works (Manoj et al., 2016) showed that DROS are the reaction
mainstay in cytochrome P450 mediated metabolism and that they play significant roles in explaining several unexplained
physiologies.
Objective: Herein, we strive to detail the thermodynamic and kinetic foundations of murburn precepts of cytochrome
P450 mediated drug metabolism.
Methods: Primarily, in silico approaches (using pdb crystal structure files), murburn reaction chemistry logic
and thermodynamic calculations to elucidate the new model of CYP-mediated drug metabolism. The theoretical
foundations are used to explain experimental observations.
Results: We visually elucidate how murburn model better explains- (i) promiscuity of the unique P450-reductase;
(ii) prolific activity and inhibitions of CYP3A4; (iii) structure-function correlations of important key
CYP2 family isozymes- 2C9, 2D6 and 2E1; and (iv) mutation studies and mechanism-based inactivation of
CYPs. Several other miscellaneous aspects of CYP reaction chemistry are also addressed.
Conclusion: In the light of our findings that DROS are crucial for explaining reaction outcomes in mXM, approaches
for understanding drug-drug interactions and methodologies for lead drug candidates' optimizations
should be revisited.
