Wayne L. Backes PhD

Wayne L. Backes PhD

Professor of Pharmacology

My research has involved the cytochrome P450 system and its ability to be involved in bioactivation of both exogenous and endogenous chemicals.  My early work involved metabolism of aromatic hydrocarbons and the P450s involved in their catabolism.  My more recent research involves the role of P450s in estrogen metabolism and its link to breast cancer and the potential role of heme oxygenase-1 in increasing cancer risk.  The electron transport chain proteins found in the endoplasmic reticulum are responsible for simultaneously carrying out multiple functions – among them –drug and foreign compound metabolism through the P450 system and heme degradation through heme oxygenase (HO-1). Both systems receive the necessary electrons from a common protein partner, NADPH-P450 reductase (POR).  As the relative concentration of POR is limiting in most tissues; both HO-1 andP450 must effectively compete for [POR] or be metabolically silent.  HO-1 levels are highly inducible by exposure to various sources, including numerous chemicals, and disease states that produce oxidative stress.  Induction can increase the [HO-1] from very low levels to those that exceed the total[POR].  Expression of var­ious P450enzymes is also affected by exposure to numerous drugs, alcohol, and pollutants.  Therefore, varia­tions in the expression of HO-1 and different P450s change their relative levels when compared to the [POR].  Although the HO-1and P450 systems are intertwined due to their common electron donor, the systems generally have been studied separately. Consequently, changes in HO-1 expression can potentially affect P450function, and con­versely changes in P450 expression can influence HO-1.  Two potential mechanisms for this effect include: (1) HO-1 and P450 compete for POR, and (2) HO-1 and P450 may form physical complexes that affect function. We plan to examine this phenomenon by testing the general hypothesis: The presence of HO-1 affects P450 function by physical complex formation with specific P450 enzymes.  The goal of this proposal is to characterize POR,HO-1, and P450 interactions in membranes, and to under­stand their functional consequences.  As a test of this hypothesis, we will focus on several P450 enzymes that catalyze estrogens.  Estradiol (E2) is catabolized byP450-dependent hydroxylation, primarily to 2-hydroxyl E2 (2-OH-E2) and4-hydroxyl E2 (4-OH-E2).  Different P450sare responsible for the generation of these metabolites with CYP1A1, CYP1A2,and CYP3A4 responsible for 2-OH-E2, and CYP1B1 for the carcinogenic4-OH-E2.  Because CYP1A2 is specifically expressed in liver, versus CYP1A1 in extrahepatic tissues, conversion of E2 is governed by the P450s in different tissues.  In liver, 2-OH-E2 production is catalyzed primarily by CYP1A2 and CYP3A4, whereas in extrahepatic tissues such as lung and breast, 2-OH-E2 is generated by CYP1A1and CYP3A.  4-OH-E2 is formed primarily by CYP1B1 in both liver and extrahepatic tissues.  

Education: B.A. Chemistry, Western Maryland College; Ph.D. Biochemistry, West Virginia University; postdoctoral, Pharmacology University of Connecticut Health Center

ORCID Identifier: https://orcid.org/0000-0002-9892-6877

MyNCBI Link: http://www.ncbi.nlm.nih.gov/sites/myncbi/wayne.backes.1/bibliography/40376466/public/?sort=date&direction=ascending.

Selected Publications:

Reed,J.R. and Backes, W.L. (2017) Physical studies of P450-P450 interactions: Predicting quaternary structures of P450 complexes in membranes from their X-ray crystal structures, Frontiers of Pharmacology, https://doi.org/10.3389.fphar.2017.00028 (PMCID: PMC5276844).

 

Pandey,A.V., Henderson, C.J., Ishii, Y., Dranendonk, M., Backes, W.L., Zanger, U.M.(2017) Editorial: Role of protein-protein interactions in metabolism: Genetics, structure, function.  Frontiers in Pharmacology https://doi.org/10.3389/fphar.2017.00881.  PMCID PMC5712015).

 

Connick,J.P., Reed, J.R., and Backes, W.L. (2018) Characterization of interactions among CYP1A2, CYP2B4, and NADPH-cytochrome P450 reductase: Identification ofspecific protein complexes. Drug Metabolism and Disposition 46, 197-203. DOI: https://doi.org/10.1124/dmd.117.078642; PMCID:PMC5797933

 

Harmon ,A.C., Hebert, V.Y., Cormier, S.A., Subramanian, B., Reed, J.R., Backes, W.L., and Dugas, T.R. (2018) Particulate matter containing environmentally persistent free radicals induces AhR-dependent cytokine and reactive oxygen species production in human bronchial epithelial cells. PLoS One 13, e0205412. https://doi.org/10.1371/journal.pone.0205412; PMCID:PMC6182347  

 

Connick,J.P., Reed, J.R., Cawley, G.F., and Backes, W.L. (2020)  Heme oxygenase-1 affects cytochrome P450function through the formation of heteromeric complexes: Interactions betweenCYP1A2 and heme oxygenase-1. J. Biol. Chem. 296, 100030; PMCID PMC7948974; https://doi.org/10.1074/jbc.RA120.015911.

 

Connick,J.P., Reed, J.R., Cawley, G.F., and Backes, W.L. (2021) Heteromeric complex formationbetween human cytochrome P450 CYP1A1 and heme oxygenase-1.  Biochem. J. 478, 377-388; DOI: https://doi.org/10.1042/BCJ20200768; PMCID: PMC8552777

 

Saha,A., Reed, J.R., Lott, C.S., and Backes, W.L. (2021) Identification of the contact region for the CYP1A2•CYP1A2 complex: The region proximal to the heme disrupts its interaction with P450 reductase. Biochemical Journal478, 2163-2178, DOI https://doi.org/10.1042/BCJ20210269; PMCID:PMC8522333

 

Reed,J.R., Guidry, J.J., and Backes, W.L. (2022) Proteomicand bioinformatics analysis of membrane lipid domains after Brij 98solubilization of uninduced and phenobarbital-induced rat liver microsomes:Defining the membrane localization of the P450 enzyme system.  Drug Metabolism and Disposition 50, (4) 374-385; DOI: https://doi.org/10.1124/dmd.121.000752; (NIHMS1797558).

 

Keywords: Cytochrome P450; P450-P450 interactions; hemeoxygenase-1; protein-proteins interactions; enzyme mechanism

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