Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications

Abstract

Enzymes in the cytochrome P450 4 (CYP4) family are involved in the metabolism of fatty acids, xenobiotics, therapeutic drugs, and signaling molecules, including eicosanoids, leukotrienes, and prostanoids. As CYP4 enzymes play a role in the maintenance of fatty acids and fatty-acid-derived bioactive molecules within a normal range, they have been implicated in various biological functions, including inflammation, skin barrier, eye function, cardiovascular health, and cancer. Numerous studies have indicated that genetic variants of CYP4 genes cause inter-individual variations in metabolism and disease susceptibility. Genetic variants of CYP4A11, 4F2 genes are associated with cardiovascular diseases. Mutations of CYP4B1, CYP4Z1, and other CYP4 genes that generate 20-HETE are a potential risk for cancer. CYP4V2 gene variants are associated with ocular disease, while those of CYP4F22 are linked to skin disease and CYP4F3B is associated with the inflammatory response. The present study comprehensively collected research to provide an updated view of the molecular functionality of CYP4 genes and their associations with human diseases. Functional analysis of CYP4 genes with clinical implications is necessary to understand inter-individual variations in disease susceptibility and for the development of alternative treatment strategies.

CYP4F13 is the Major Enzyme for Conversion of alpha-Eleostearic Acid into <i>cis</i>-9, <i>trans</i>-11-Conjugated Linoleic Acid in Mouse Hepatic Microsomes

“…In addition, we found no inhibitory effect from the other CYP4F substrates at low concentrations except for PGA 1 , which is one of the classical substrates of CYP4F enzymes, since other CYP4F-substrates could also be catalyzed by other CYP family enzymes besides CYP4F. Taken together, these findings led us to select CYP4F isoforms as α-ESA saturase, consistent with previous reports showing that CYP4As metabolize intermediatechain fatty acids fatty acids with C10 to 16 carbon chain 29 , while CYP4Fs catalyze long-chain fatty acids C16 to 26 53 . However, we could not determine the specific CYP4F enzyme involved due to a lack of a selective marker substrate for the activity of individual CYP4F enzymes in the study of the effect of CYP-substrates on CLA formation, although PGA 1 could be used as a nonselective marker substrate for CYP4F enzymes.…”

“…The results showed that the inhibitors of CYP 1 38 , 2 39,40 , and 3 41 family enzymes had minimal or modest inhibitory activities. However, CYP1-3 contain major xenobiotic-metabolizing enzymes responsible for the metabolism of the majority of drugs and other xenobiotics 42,43 , while CYP4 enzymes typically metabolize fatty acids 29,44 .…”

“…However, the precise metabolic pathway and enzyme involved have not been identified yet. The superfamily of cytochrome P450 CYP enzymes is considered the major enzyme family responsible for the phase I metabolism reduction, oxidation, or hydrolysis reactions of numerous endogenous and exogenous compounds, such as drugs and other xenobiotics 29 . The in vivo reactions catalyzed by CYP enzymes require the cofactor NADPH as the electron source and the redox partner of cytochrome P450 reductase CPR , which functions in the electron transfer from NADPH to CYP in microsomes 30 .…”

Early pregnancy maternal progesterone administration alters pituitary and testis function and steroid profile in male fetuses

“…This dataset, from a separate study, consisted of hepatic RNAseq analysis performed on control fetal female and male livers at a slightly later gestation (gestational D90). Expression of hepatic progesterone metabolising enzymes CYP3A4 , CYP2C9 , CYP2C19 21 , 22 and xenobiotic metabolising enzymes CYP2C18, CYP2J2 and CYP4F11 23 , 24 were decreased in fetal males as compared with fetal females (Fig. 2 a–f; P < 0.05–0.001).…”

Global Gene Expression Profiling of Body-Mass Index in Middle-Aged Danish Twins

“…For the third gene in (Table 1), PAX8, differential DNA methylation was identified to associate with gestational famine exposure and metabolic traits [28]. Other interesting genes linked to top probes of ( Table 1) include PPP1R3A whose SNP variation has been associated with risk of type 2 diabetes and CYP4F12 which belongs to the cytochrome P450 4 (CYP4) family implicated in various biological functions including inflammation, cardiovascular health, and cancer [29,30].…”