Preface

James P. Hardwick, Department of Integrative Medical Sciences, Northeast Medical University, Rootstown, Ohio, USA

Cytochrome P450s (CYPs) are critical monooxygenase enzymes in the synthesis and degradation of both endogenous and exogenous substrates that influence cellular homeostasis through regulation of cellular metabolism, growth, differentiation, apoptosis, and neuroendocrine function. To date, over 23 human diseases are associated with mutations in members of the 18 CYP families (Nebert, Wikvall, & Miller, 2013). Furthermore, variants of human CYP genes have a profound effect on drug and endogenous metabolite levels by altering drug therapeutic efficacy or drug toxicity.

Unfortunately, the functional role of CYP isoforms and genetic variants in complex human diseases through altered metabolism of endogenous substrates has been largely unexplored. Several genome-wide association studies (GWAS) have revealed that genetic variations of CYP1, CYP2, CYP3, CYP4, and CYP7 families are associated with significant individual risk for complex polygenic human disease. This is apparent when one considers the fact that CYP members participate in the metabolism of fatty acid, cholesterol, and bile acid pathways, in addition to modulating vitamin A, vitamin D, vitamin K, vitamin E, and eicosanoid metabolic pathways. The association of an individual's P450 profile to complex human diseases becomes a formidable scientific task because of the broad substrate specificity of individual P450s, differential regulation of CYP genes by multiple nuclear hormone receptors, and the role of polymorphic CYP variants in the metabolism of endogenous and exogenous compounds. However, the system biology approaches with new technologies to measure CYP copy number variation (CNV), the level of variant CYP expression by digital PCR, quantitative proteomic P450 analysis (MacLeod et al., 2015; Sakamoto et al., 2011), and metabolomics analysis of endogenous substrate metabolism by mass spectrometry (Guengerich, Tang, Cheng, & Salamanca-Pinzon, 2011; Xiao & Guengerich, 2012) have new avenues to associate CYP variants with altered endogenous metabolites to complex polygenetic human disease.

This Advances in Pharmacology volume on the role of CYP in inflammation and cancer compiles a comprehensive collection of monographs on the role of different CYP gene families in human susceptibility, initiation, and progression of inflammation and cancer. Extraordinary progress has been made by the authors within this volume on the identification of and the role of the 57 human P450s from 18 CYP gene families, including the correlation of CYP polymorphic variants with inflammatory disorders and initiation and progression of cancer. Although variants of the CYP1, CYP2C, CYP2A6, CYP2A6, CYP2B6, CYP2D6, CYP2E, CYP3A, and CYP7A families have been associated with individual increased risk of cancer through alteration in metabolism and drug susceptibility from animal studies, the association of human CYP variant alleles with these diseases lacks proof because of subpar statistical power from GWAS. Therefore, it is difficult to conclusively associate human studies with transgenic and knockout animal data, even though many published GWAS have found positive correlations between several CYP family members and several complex human diseases. It is refreshing that the contributors to this volume not only provide a comprehensive detailed analysis of the functional and pharmacological role of different CYP families in inflammation and cancer but also offer insightful theories and experimental plans to associate an individual's CYP genotype with disease phenotype in complex human diseases.

In review one by Bruce Wahlang, Cameron Falkner, Matt Cave, and Russell Prough, the authors discuss the historical significance and background of CYP in the activation of procarcinogens that are genotoxic agents forming DNA adducts that lead to DNA mutations. They also provide insight into how chemotherapeutic prodrugs are used in cancer chemotherapy through metabolism by selective members of the CYP family. The authors offer a personalized medical approach in the treatment of cancer. By understanding the expression pattern of an individual's CYP genes in different tissue tumors, the authors suggest efficacy of many chemotherapeutic drugs can be increased if we increase the expression of the tumor CYP through activation of nuclear hormone receptors with coadministration of chemotherapeutic prodrugs metabolized by these induced CYP. By using this theoretical approach, one can design therapies with increased chemotherapeutic efficacy and reduced drug toxicity. Lastly, the authors discuss the role of P450 polymorphic variants in cancer susceptibility and how informatics approaches, combining CYP genomic, proteomics, and metabolomics data, are being used to translate our basic understanding of CYP expression and drug metabolism into personalized cancer treatments.

In the second review, Eugene G. Hrycay and Stelvio M. Bandiera provide us with a solid foundation to understand the P450 catalytic cycle and how P450 functions as a monooxygenase or an oxidase and peroxygenase under different conditions of cellular stress can increase drug concentration or cause adverse drug–drug interactions. The outcome of this P450-related stress is increased formation of reactive oxygen species (ROS) through coupling of the P450 catalytic cycle, which eventually results in increased endoplasmic reticulum (ER) lipid peroxidation and initiation of ER unfolded response to reestablish cellular homeostasis. The uncoupling of the P450 cycle is also discussed by the authors extensively, citing three models of uncoupling: (1) substrate-dependent access of water that destabilizes the ferric-superoxo intermediate, (2) reduction of the ferric-peroxo intermediate, and (3) dissociation of the hyperoxide anion from ferric iron leading to generation of hydrogen peroxide. The uncoupling of electron transport to substrate oxidation by different members of the CYP gene families varies significantly, ranging from 0.5% to greater than 50%, indicating that a specific P450 isozyme can play a significant role in the generation of ROS. It is presently unknown whether these P450s have the functional role in providing an oxidizing environment necessary for ER protein unfolding. In any case, CYP enzymes are quantitatively one of the most important cellular sources of ROS and thus have an important role in the initiation and propagation of lipid peroxidation. The ultimate consequence of increased polyunsaturated fatty acid lipid peroxidation is the formation of fatty acid peroxides, which can function as chemotactic agents to attract immune cells to the site of injury and initiate the inflammatory response. Thus, the persistent uncoupling of selective P450 isozymes by drugs or through increased expression can contribute to chronic inflammation with the consequences of an observable pathology in numerous disease processes. It is very apparent that CYP isoforms have a pivotal role in initiating the acute inflammatory response by endogenous or exogenous substrates capable of uncoupling the P450 catalytic cycle. To ameliorate adverse drug reaction and the consequence of idiosyncratic drug interaction would require choosing either a drug not metabolized by the same CYP or a drug with the ability to act as a reducing agent (e.g., antioxidant) and thus prevent CYP catalytic cycle uncoupling and ROS formation. Of course, in the design of chemotherapeutic agents the reverse scenario may increase the efficacy of combination chemotherapeutic drug therapy.

The third review by Ann Daly details our current understanding of the relevance of polymorphic CYP variants in disease initiation, progression, and individual susceptibility to cancer. Present-day dogma generated solely from genomic data suggests that dominance variation at common SNPs explains only a small fraction of phenotypic variation for complex human diseases or the role of CYP variants in cancer susceptibility. The formation of either sporadic or familial inherited SNP plays a substantial role in inflammation and cancer only if the metabolite has a critical central role in complex human diseases. This is very evident in arginine mutations of isocitrate dehydrogenases (IDH1 and IDH2) in colorectal, glioma, and acute myeloid leukemia. These mutations lead to conversion of α-ketoglutarate to R-2-hydroxyglutarate metabolite that inhibits α-ketoglutarate-dependent enzymes of the tricarboxylic cycle and mitochondrial respiratory chain inhibition of cytochrome c oxidase (complex IV) and ATP synthase (complex V). This results in the induction of antiapoptotic BCL-2 that antagonizes cell death signaling. Until we can discern the phenotype caused by variant CYP in producing new drug and/or endogenous biochemical metabolite, the associate of variant CYP with individual susceptibility to complex human disease will not be realized. This is demonstrated in the...