Comparison on Metabolism of Estradiol and Its 17-Sulfate by Recombinant Human CYP Isoforms

AbstractGiven the strong trend to implement zebrafish (Danio rerio) embryos as translational model not only in ecotoxicological, but also toxicological testing strategies, there is an increasing need for a better understanding of their capacity for xenobiotic biotransformation. With respect to the extrapolation of toxicological data from zebrafish embryos to other life stages or even other organisms, qualitative and quantitative differences in biotransformation pathways, above all in cytochrome P450-dependent (CYP) phase I biotransformation, may lead to over- or underestimation of the hazard and risk certain xenobiotic compounds may pose to later developmental stages or other species. This review provides a comprehensive state-of-the-art overview of the scientific knowledge on the development of the CYP1-4 families and corresponding phase I biotransformation and bioactivation capacities in zebrafish. A total of 68 publications dealing with spatiotemporal CYP mRNA expression patterns, activities towards mammalian CYP-probe substrates, bioactivation and detoxification activities, as well as metabolite profiling were analyzed and included in this review. The main results allow for the following conclusions: (1) Extensive work has been done to document mRNA expression of CYP isoforms from earliest embryonic stages of zebrafish, but juvenile and adult zebrafish have been largely neglected so far. (2) There is insufficient understanding of how sex- and developmental stage-related differences in expression levels of certain CYP isoforms may impact biotransformation and bioactivation capacities in the respective sexes and in different developmental stages of zebrafish. (3) Albeit qualitatively often identical, many studies revealed quantitative differences in metabolic activities of zebrafish embryos and later developmental stages. However, the actual relevance of age-related differences on the outcome of toxicological studies still needs to be clarified. (4) With respect to current remaining gaps, there is still an urgent need for further studies systematically assessing metabolic profiles and capacities of CYP isoforms in zebrafish. Given the increasing importance of Adverse Outcome Pathway (AOP) concepts, an improved understanding of CYP capacities appears essential for the interpretation and outcome of (eco)toxicological studies.

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The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3sg66 ◽

2008 ◽

Vol 11 (1) ◽

pp. 147 ◽

Cited By ~ 45

Author(s):

Marwa E. Elsherbiny ◽

Ayman O.S. El-Kadi ◽

Dion R. Brocks

Keyword(s):

Cytochrome P450 ◽

Inhibitory Effect ◽

Intrinsic Clearance ◽

Significant Inhibition ◽

Inhibitory Influence ◽

Relative Kinetic ◽

Cyp Isoforms ◽

High Concentrations ◽

In Vivo Administration

PURPOSE. To evaluate the metabolism of amiodarone (AM) to desethylamiodarone (DEA) by selected human and rat cytochrome P450, and the inhibitory effect of ketoconazole (KTZ). METHODS. Some important CYP isoenzymes (rat CYP1A1, 1A2, 2C6, 2C11, 2D1, 2D2, and 3A1 and human CYP1A1, 1A2, 2D6 and 3A4) were spiked with various concentrations of AM to determine the relative kinetic parameters for formation of DEA in the presence and absence of various concentrations of KTZ. RESULTS. The formation of DEA was observed when AM was exposed to each of the CYP tested, although the rates were varied. Human CYP1A1 followed by 3A4 had the highest intrinsic clearance (CLint) for DEA formation whereas in rat, CYP2D1 followed by CYP2C11 had the highest CLint. Human and rat CYP1A2 seemed to have the lowest CLint. At high concentrations of AM and KTZ, near those expected in vivo, significant inhibition of all isoforms except for rat CYP1A2 was observed. At lower concentration ranges of both drugs, the inhibitory constant was determined. At these levels, KTZ was found to potently inhibit human CYP1A1 and 3A4 and rat 2D2 and 1A1. CONCLUSION. Human CYP1A1 and 3A4 and rat CYP2D1 and 2C11 were most efficient in converting AM to DEA. For DEA formation, the in vivo administration of KTZ could inhibit other CYP isoforms besides CYP3A in human and rat.

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Selective Inhibition of Bakuchicin Isolated fromPsoralea corylifoliaon CYP1A in Human Liver Microsomes

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/5198743 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Sun Joo Kim ◽

Heung Chan Oh ◽

Youn-Chul Kim ◽

Gil-Saeng Jeong ◽

Sangkyu Lee

Keyword(s):

Human Liver ◽

Competitive Inhibition ◽

Biological Activities ◽

Biological Effects ◽

Liver Microsomes ◽

Selective Inhibition ◽

Human Liver Microsomes ◽

Inhibition Mechanism ◽

Inhibitory Effects ◽

Cyp Isoforms

Bakuchicin is a furanocoumarin isolated fromPsoralea corylifoliaand shows several biological activities. Although there have been studies on the biological effects of bakuchicin, its modulation potency of CYP activities has not been previously investigated. Here, we investigated the inhibitory effects of bakuchicin on the activities of CYP isoforms by using a cocktail of probe substrates in pooled human liver microsomes (HLMs) and human recombinantcDNA-expressedCYP. Bakuchicin strongly inhibited CYP1A-mediated phenacetinO-deethylation with an IC50value of 0.43 μM in HLMs. It was confirmed by human recombinantcDNA-expressedCYP1A1 and CYP1A2 with aKivalue of 0.11 μM and 0.32 μM, respectively. A Lineweaver-Burk plot indicated that the inhibition mechanism of bakuchicin was competitive inhibition. Overall, this is the first study to investigate the potential CYP1A1 and CYP1A2 inhibition associated with bakuchicin and to report its competitive inhibitory effects on HLMs.

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In vitro biotransformation of tris(1,3-dichloro-2-propyl) phosphate and triphenyl phosphate by mouse liver microsomes: Kinetics and key CYP isoforms

Chemosphere ◽

10.1016/j.chemosphere.2021.132504 ◽

2021 ◽

pp. 132504

Author(s):

Mei-Hong Chen ◽

Sheng-Hu Zhang ◽

Shi-Ming Jia ◽

Li-Jun Wang ◽

Wan-Li Ma

Keyword(s):

Mouse Liver ◽

Liver Microsomes ◽

Triphenyl Phosphate ◽

Cyp Isoforms

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Modification of the anticancer drug tamoxifen to avoid CYP2D6 polymorphism

Canadian Journal of Chemistry ◽

10.1139/cjc-2012-0537 ◽

2013 ◽

Vol 91 (9) ◽

pp. 916-924

Author(s):

Li Gao ◽

Xianqiang Sun ◽

Yaoquan Tu ◽

Hans Ågren ◽

Leif A. Eriksson

Keyword(s):

Dna Adducts ◽

Formation Enthalpy ◽

Active Metabolites ◽

Cyp2d6 Polymorphism ◽

Cyp2d6 Activity ◽

Quantum Chemistry Calculations ◽

Wide Range ◽

Reaction Energies ◽

Cyp Isoforms ◽

Treat Breast Cancer

The prodrug tamoxifen (TAM) is the most widely used drug to treat breast cancer, and is metabolised to the active 4-hydroxy derivatives dominantly by hepatic CYP2D6. However, the application to patients with different polymorphic CYP2D6 has been under debate, because the efficacy of TAM is suspected to be suppressed in patients who have diminished CYP2D6 activity, resulting in inadequate active metabolites. We here propose modified structures, such as 4-methylTAM, which is highly possible to be activated by CYP3A, the most abundant CYP isoforms in the liver, whereby the genetic polymorphism of CYP2D6 is avoided. The diversity of CYP catalyzed metabolic paths for TAM and its derivatives are studied by quantum chemistry calculations on the reaction energies of the initial H atom abstraction steps. The ability of forming DNA adducts is compared through the formation enthalpy of the carbocation intermediate. The results suggest that the modified structures are safe with regard to forming DNA adducts and may be used as prodrugs in a wide range of patients, due to CYP3A, rather than CYP2D6, mediated activation.

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β-Naphthoflavone and Ethanol Reverse Mitochondrial Dysfunction in A Parkinsonian Model of Neurodegeneration

International Journal of Molecular Sciences ◽

10.3390/ijms21113955 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3955

Author(s):

Jesus Fernandez-Abascal ◽

Elda Chiaino ◽

Maria Frosini ◽

Gavin P. Davey ◽

Massimo Valoti

Keyword(s):

Complex I ◽

In Vitro Model ◽

Inhibitory Effects ◽

Cyp Induction ◽

Cyp Isoforms ◽

Vitro Model ◽

Complex I Activity ◽

Cyp 2D6

The 1-methyl-4-phenylpyridinium (MPP+) is a parkinsonian-inducing toxin that promotes neurodegeneration of dopaminergic cells by directly targeting complex I of mitochondria. Recently, it was reported that some Cytochrome P450 (CYP) isoforms, such as CYP 2D6 or 2E1, may be involved in the development of this neurodegenerative disease. In order to study a possible role for CYP induction in neurorepair, we designed an in vitro model where undifferentiated neuroblastoma SH-SY5Y cells were treated with the CYP inducers β-naphthoflavone (βNF) and ethanol (EtOH) before and during exposure to the parkinsonian neurotoxin, MPP+. The toxic effect of MPP+ in cell viability was rescued with both βNF and EtOH treatments. We also report that this was due to a decrease in reactive oxygen species (ROS) production, restoration of mitochondrial fusion kinetics, and mitochondrial membrane potential. These treatments also protected complex I activity against the inhibitory effects caused by MPP+, suggesting a possible neuroprotective role for CYP inducers. These results bring new insights into the possible role of CYP isoenzymes in xenobiotic clearance and central nervous system homeostasis.

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Pharmacokinetics of mirodenafil, a new erectogenic, and its metabolite, SK3541, in rats: involvement of CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 for the metabolism of both mirodenafil and SK3541

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3688m ◽

2010 ◽

Vol 13 (1) ◽

pp. 93 ◽

Cited By ~ 5

Author(s):

Young Hee Choi ◽

Young Sun Lee ◽

Myung Gull Lee ◽

Tae Kon Kim ◽

Bong-Yong Lee

Keyword(s):

Hepatic Microsomes ◽

Renal Clearances ◽

Cyp Isoforms

Purpose. This study was performed to find which types of hepatic CYP isoforms are responsible for the metabolism of mirodenafil (a new erectogenic) and one of its metabolite, SK3541, using various hepatic CYP inducers and inhibitors in rats. Methods. Mirodenafil at a dose of 20 mg/kg was administered intravenously to control rats and rats pretreated with various CYP inducers and inhibitors. The disappearance of SK3541 was also measured in vitro hepatic microsomes of rats with and without CYP inducer and inhibitors. Results. Compared to controls, in rats pretreated with 3-methylcholanthrene, orphenadrine, and dexamethasone (main inducers of CYP1A1/2, 2B1/2, and 3A1/2, respectively), the non-renal clearances (CLNRs) of mirodenafil were significantly faster (by 39.4%, 59.3%, and 63.9%, respectively). However, compared to controls, in rats pretreated with quinine and troleandomycin (main inhibitors of CYP2D subfamily and 3A1/2, respectively), the CLNRs of mirodenafil were significantly slower (by 36.1% and 33.2%, respectively). In rat hepatic microsomes spiked with furafylline, quinine, and troleandomycin (main inhibitors of CYP1A2, 2D subfamily, and 3A1/2, respectively), the intrinsic clearances (CLints) for the disappearance of SK3541 were significantly slower (by 18.4%, 35.3%, and 51.5%, respectively) than controls. Also in rat hepatic microsomes pretreated with orphenadrine (a main inducer of CYP2B1/2), the CLint for the disappearance of SK3541 was significantly faster (by 55.5%) than controls. Conclusions. The above data suggest that hepatic CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 are involved in the metabolism of both mirodenafil and SK3541 in rats.

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