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The activation of pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) can induce liver enlargement. Recently, we reported that PXR or PPARα activation-induced hepatomegaly depends on yes-associated protein (YAP) signaling and is characterized by hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. However, it remains unclear whether PXR or PPARα activation-induced hepatomegaly can be reversed after the withdrawal of their agonists. In this study, we investigated the regression of enlarged liver to normal size following the withdrawal of PCN or WY-14643 (typical agonists of mouse PXR or PPARα) in C57BL/6 mice. The immunohistochemistry analysis of CTNNB1 and KI67 showed a reversal of hepatocyte size and a decrease in hepatocyte proliferation after the withdrawal of agonists. In details, the expression of PXR or PPARα downstream proteins (CYP3A11, CYP2B10, ACOX1, and CYP4A) and the expression of proliferation-related proteins (CCNA1, CCND1, and PCNA) returned to the normal levels. Furthermore, YAP and its downstream proteins (CTGF, CYR61, and ANKRD1) also restored to the normal states, which was consistent with the change in liver size. These findings demonstrate the reversibility of PXR or PPARα activation-induced hepatomegaly and provide new data for the safety of PXR and PPARα as drug targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cytochrome P450 monooxygenases (P450s) constitute a large superfamily of heme-thiolate proteins that are involved in the biosynthesis or degradation of endogenous compounds and detoxification of exogenous chemicals. It has been reported that P450s could serve as odorant-degrading enzymes (ODEs) to inactivate odorants to avoid saturating the antennae. However, there is little information about P450s in the antennae of Locusta migratoria. In the current work, we conducted an antenna transcriptome analysis and identified 92 P450s, including 68 full-length and 24 partial sequences. Phylogenetic analysis showed that 68 full-length P450s were grouped into four clans: CYP2, CYP3, CYP4, and mitochondria clans. Tissue, stage, and sex-dependent expressions of these 68 P450s were investigated. The results showed that 4 P450s were antenna-specific, whereas others were antenna-rich but also expressed in other tissues, implying their various potential roles in the antennae. In addition, the responses of seven selected P450s to five gramineous plant volatiles and four locust volatiles were determined. CYP6MU1 could be induced by almost all compounds tested, suggesting its important roles in odorant processing. Different P450s exhibited diverse responses to odorants, indicating that specific regulation of P450 expression by odorants might modulate the sensitivity of the olfactory responses to various chemicals., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The skin permeability barrier is indispensable for maintaining water inside the body and preventing the invasion of pathogens and allergens; abnormalities lead to skin disorders such as atopic dermatitis and ichthyosis. Acylceramide is an essential lipid for skin barrier formation, and CYP4F22 is a fatty acid ω-hydroxylase involved in its synthesis. Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis, although the symptoms vary among mutation sites and types. Here, we generated knockout mice deficient in Cyp4f39, the mouse ortholog of human CYP4F22, to investigate the effects of completely abrogating the function of the fatty acid ω-hydroxylase involved in acylceramide production on skin barrier formation. Cyp4f39 knockout mice died within 8 hours of birth. Large increases in transepidermal water loss and penetration of a dye from outside the body were observed, indicating severe skin barrier dysfunction. Histologic analyses of the epidermis revealed impairment of lipid lamella formation, accumulation of corneodesmosomes in the stratum corneum, and persistence of periderm. In addition, lipid analyses by mass spectrometry showed almost complete loss of acylceramide and its precursor ω-hydroxy ceramide. In conclusion, our findings provide clues to the molecular mechanisms of skin barrier abnormalities and the pathogenesis of ichthyosis caused by Cyp4f39 and CYP4F22 by association., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Hepatic carboxylesterases (Ces) catalyze the metabolism of drugs, environmental toxicants, and endogenous lipids and are known to be regulated by multiple nuclear receptors. Perfluorooctanoic acid (PFOA) is a synthetic fluorochemical that has been associated with dyslipidemia in exposed populations. In liver, PFOA can activate nuclear receptors such as PPARα, and alter the metabolism and excretion of chemicals. Here, we sought to test the ability of PFOA to modulate Ces expression and activity in the presence and absence of the PPARα receptor. For this purpose, male C57BL/6 NCrl mice were administered PFOA (1 or 3 mg/kg, po, 7 days) and livers collected for assessment of Ces expression and activity. PFOA increased Ces1 and 2 protein and activity. Notably, PFOA increased Ces1d, 1e, 1f, 1 g, 2c, and 2e mRNAs between 1.5- and 2.5-fold, while it decreased Ces1c and 2b. Activation of PPARα by PFOA was confirmed by up-regulation of Cyp4a14 mRNA. In a separate study of PFOA-treated wild-type (WT) and PPARα-null mice, induction of Ces 1e and 1f mRNA and in turn, Ces1 protein, was PPARα-dependent. Interestingly, in PPARα-null mice, Ces1c, 1d, 1 g, 2a, 2b, and 2e mRNAs and Ces2 protein were up-regulated by PFOA which contributed to sustained up-regulation of Ces activity, although to a lower extent than observed in WT mice. Activation of the CAR and PXR receptors likely accounted for up-regulation of select Ces1 and 2 subtypes in PPARα-null mice. In conclusion, the environmental contaminant PFOA modulates the expression and function of hepatic Ces enzymes, in part through PPARα., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The initial studies of the metabolism of arachidonic acid (AA) by the cytochrome P450 (P450) hemeproteins sought to: a ) elucidate the roles for these enzymes in the metabolism of endogenous pools of the FA, b ) identify the P450 isoforms involved in AA epoxidation and ω/ω-1 hydroxylation, and c ) explore the biological activities of their metabolites. These early investigations provided a foundation for subsequent efforts to establish the physiological relevance of the AA monooxygenase and its contributions to the pathophysiology of, for example, cancer, diabetes, hypertension, inflammation, nociception, and vascular disease. This retrospective analyzes the history of some of these efforts, with emphasis on genetic studies that identified roles for the murine Cyp4a and Cyp2c genes in renal and vascular physiology and the pathophysiology of hypertension and cancer. Wide-ranging investigations by laboratories worldwide, including the authors, have established a better appreciation of the enzymology, genetics, and physiologic roles for what is now known as the third branch of the AA cascade. Combined with the development of analytical and pharmacological tools, including robust synthetic agonists and antagonists of the major metabolites, we stand at the threshold of novel therapeutic approaches for the treatment of renal injury, pain, hypertension, and heart disease., (Copyright © 2018 Capdevila and Falck.)

Angiotensin II (AngII) plays an important role in the pathogenesis of hypertension and associated renal injuries. To elucidate the molecular mechanism by which AngII induces renal damage, we found that AngII infusion significantly induced CYP4A14 expression in renal proximal tubule cells (RPTCs) with marked increases in blood pressure and proteinuria. Renal production of the major CYP4A metabolite, 20-HETE, was also significantly increased in the AngII-treated mice. Compared to wild-type (WT) mice, CYP4A14 knockout (CYP4A14 -/- ) mice exhibited significantly lower levels of blood pressure, renal 20-HETE production, proteinuria and renal fibrosis following AngII infusion. Furthermore, AngII-induced renal expression of profibrotic genes and proinflammatory genes was significantly attenuated in CYP4A14 -/- mice. In vitro studies using cultured RPTCs demonstrated that AngII significantly induced CYP4A14 expression and 20-HETE production via the MAPK signaling pathway. AngII treatment increased TGF-β and collagen expression, which was attenuated by the CYP4A inhibitor, TS-011. Moreover, 20-HETE treatment potently induced CYP4A14 expression and TGF-β and collagen levels. Collectively, these findings suggest that attenuated renal fibrosis in AngII-treated CYP4A14 -/- mice may result from both reduced systemic blood pressure and renal 20-HETE production. Therefore, CYP4A14 may represent a useful target for the treatment of AngII-associated renal damage., (Copyright © 2017 Elsevier B.V. All rights reserved.)

CYP4F11, together with CYP4F2, plays an important role in the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. We identified 21 variants by whole exome sequencing, including 4 non-synonymous variants in Korean subjects. The proteins of the wild-type CYP4F11 and the four coding variants (C276R, D315N, D374Y, and D446N) were expressed in Escherichia coli DH5α cells and purified to give cytochrome P450-specific carbon monoxide difference spectra. Wild-type CYP4F2 was also expressed and purified to compare its activity with the CYP4F11 wild-type. Wild-type CYP4F11 exhibited the highest maximal clearance for erythromycin N-demethylase activity followed by the variants D374Y, D446N, C276R, and D315N. In particular, the CYP4F11 D315N protein showed about 50% decrease in intrinsic clearance compared to the wild type. The ability of wild-type CYP4F11 and the variants to synthesize 20-HETE from arachidonic acid was similar; the CYP4F11 D315N variant, however, showed only 68% of wild-type activity. Furthermore, the ability of CYP4F2 to synthesize 20-HETE was 1.7-fold greater than that of CYP4F11. Overall, our results suggest that the metabolism of CYP4F11 substrates may be reduced in individuals carrying the CYP4F11 D315N genetic variant and individuals carrying the common D446N CYP4F11 variant likely exhibit comparable 20-HETE synthesis as individuals expressing wild-type CYP4F11., (Copyright © 2017. Published by Elsevier Inc.)

Purpose: The contribution of cytochrome P450 (CYP) gene expressions in metabolic syndrome (MetS) has not been elucidated, and was the aim of this study., Methods: A total of 51 MetS patients and 41 healthy controls with similar age and sex were included to this study. mRNA from blood samples was extracted, and real-time polymerase chain reaction was performed for gene expressions using a dynamic array system., Results: We observed marked suppressions in CYP2A6 (p=0.0123), CYP4F2 (p=0.0005), CYP3A5 (p=0.0003), and CYP17A1 (p<0.0001) gene expressions in MetS patients., Conclusions: This is the first study to provide evidence that depressed expressions of CYP2A6, CYP4F2, CYP3A5, and CYP17A1 genes may play a role in MetS., (Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

To investigate the effects of CYP4Z1 3'UTR in migration of breast cancer cells, a series of assays were used to confirm that overexpression of CYP4Z1 3'UTR could suppress the capacity of migration and adhesion of MCF-7 and MDA-MB-231 cells. EMT (Epithelial-mesenchymal transition)-related proteins were regulated by CYP4Z1 3'UTR. Mesenchyma markers like Vimentin, MMP-2, and MMP-9 were down-regulated, while the expression of E-cadherin was up-regulated with CYP4Z1 3'UTR overexpression. Notably, luciferase reporter and qRT-PCR assays were applied to verify that CYP4Z1 3'UTR was the potential target of miR-9. In addition, our results showed that CYP4Z1 3'UTR repressed the expression of E-cadherin in a miRNA-dependent manner. Combining with our previous study, we have discovered the underlying link between CYP4Z1 and E-cadherin. Therefore, those preliminary data suggest that CYP4Z1 3'UTR could inhibit the migration and EMT of breast cancer cells via acting as a ceRNA for E-cadherin., (Copyright © 2016 Elsevier Inc. All rights reserved.)