Cytochrome P450 1 Genes in Early Deuterostomes (Tunicates and Sea Urchins) and Vertebrates (Chicken and Frog): Origin and Diversification of the CYP1 Gene Family

Goldstone, Jeffrey; Goldstone, Heather M. H.; Morrison, Ann M.; Tarrant, Ann M.; Kern, Suzanne E.; Woodin, Bruce R.; Stegeman, John J.

doi:10.1093/molbev/msm200

Cited by 89 publications

(80 citation statements)

References 73 publications

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“…While evidence of deuterostome (e.g. tunicate and sea urchin) CYPlA-like and CYP1-like genes exists (Goldstone et al 2007), to date no full-length CYP -like sequences have been reported for molluscs (Rewitz et al 2006) or any other protostome, further suggesting that the CYP 1 family may be deuterostome specific. Recent work by Grosvik et al (2006) strengthens this argument by calling into question immunochemical evidence suggesting the presence of a CYP 1A-like protein in molluscs.…”

Section: Pseudopterogorgia Americana)mentioning

confidence: 99%

Functional characterization and expression of molluscan detoxification enzymes and transporters involved in dietary allelochemical resistance

Whalen¹

2008

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Understanding how organisms deal with potentially toxic or fitness-reducing allelochemicals is important for understanding patterns of predation and herbivory in the marine environment. The ability of marine consumers to tolerate dietary toxins may involve biochemical resistance mechanisms, which increase the hydrophilicity of compounds and facilitate their active efflux out of sensitive cells and tissues. While several allelochemical-responsive detoxification enzymes have been sequenced and functionally characterized in terrestrial invertebrates feeding on chemically defended host plants, there is virtually no information concerning the role of these biotransformation enzymes that may mediate feeding tolerance in marine invertebrates. The objective of this research was to assess the diversity and dietary regulation of cytochrome P450s (CYP), glutathione S-transferases (GST) and ABC transporters in the generalist marine gastropod Cyphoma gibbosum feeding on a variety of chemically defended gorgonian corals, and to identify those dietary natural products that act as substrates for these proteins.Molecular and proteomic techniques identified both allelochemically-responsive CYPs, and constitutively expressed GSTs and transporters in Cyphoma digestive glands. Inhibition of Cyphoma GST activity by gorgonian extracts and selected allelochemicals (i.e., prostaglandins) indicated that gorgonian diets are likely to contain substrates for molluscan detoxification enzymes. In vitro metabolism studies with recombinant CYPs suggested those Cyphoma enzymes most closely related to vertebrate fatty acid hydroxylating enzymes may contribute to the detoxification ofichthyodeterrent cyclopentenone prostaglandins found in abundance in selected gorgonian species. Finally, the presence and activity of multixenobiotic resistance transporters in Cyphoma and the co-occuring specialist nudibranch, Tritonia hamnerorum, suggests these efflux transporters could function as a first line of defense against dietary intoxication. Together, these results suggest marine consumers that regularly exploit allelochemicalrich prey have evolved both general (GST and ABC transporters) and allelochemicalspecific (CYP) detoxification mechanisms to tolerate prey chemical defenses.Thesis Supervisor: Mark E. Hahn Title: Senior Scientist, Biology Department, WHOI COMPLETE ABSTRACT Intense consumer pressure in tropical marine ecosystems not only structures the organization and functioning of marine communities, but has a profound effect on the phenotype of resident organisms. In order to persist in the midst of extreme predation and herbivory, sessile benthic marine organisms, afforded with no means of escape, often produce chemical defenses, termed allelochemicals, which render their tissues unpalatable or toxic to most potential consumers. Despite the fitness-reducing consequences of consuming noxious/toxic prey, less mobile consumers, frequently drawn to their hosts by the chemical refugia they provide, are able to tolerate the toxicological challe...

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Section: Pseudopterogorgia Americana)mentioning

confidence: 99%

Functional characterization and expression of molluscan detoxification enzymes and transporters involved in dietary allelochemical resistance

Whalen¹

2008

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“…This receptor, which is activated by small molecules and by light, is one of the 34 known proteins that both contain a PerArnt-Sim domain and regulate responses to environmental changes (1)(2)(3)(4). Both AHR itself and the first family of cytochrome P450 (CYP1) enzymes, whose expression is regulated by AHR, have been highly conserved during evolution (5,6). This observation, together with its presence in most cell types and during all phases of development, indicate strongly that, in addition to responses to xenobiotics, the AHR and its endogenous activators are involved in vital physiological processes.…”

mentioning

confidence: 99%

Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor

Wincent

Bengtsson²,

Bardbori³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

185

215

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Altered systemic levels of 6-formylindolo [3,2-b]carbazole (FICZ), an enigmatic endogenous ligand for the aryl hydrocarbon receptor (AHR), may explain adverse physiological responses evoked by small natural and anthropogenic molecules as well as by oxidative stress and light. We demonstrate here that several different chemical compounds can inhibit the metabolism of FICZ, thereby disrupting the autoregulatory feedback control of cytochrome P4501 systems and other proteins whose expression is regulated by AHR. FICZ is both the most tightly bound endogenous agonist for the AHR and an ideal substrate for cytochrome CYP1A1/1A2 and 1B1, thereby also participating in an autoregulatory loop that keeps its own steady-state concentration low. At very low concentrations FICZ influences circadian rhythms, responses to UV light, homeostasis associated with pro-and anti-inflammatory processes, and genomic stability. Here, we demonstrate that, if its metabolic clearance is compromised, femtomolar background levels of this compound in cell-culture medium are sufficient to up-regulate CYP1A1 mRNA and enzyme activity. The oxidants UVB irradiation and hydrogen peroxide and the model AHR antagonist 3′-methoxy-4′-nitroflavone all inhibited induction of CYP1A1 enzyme activity by FICZ or 2,3,7,8-tetrachlorodibenzo-p-dioxin, thereby subsequently elevating intracellular levels of FICZ and activating AHR. Taken together, these findings support an indirect mechanism of AHR activation, indicating that AHR activation by molecules with low affinity actually may reflect inhibition of FICZ metabolism and raising questions about the reported promiscuity of the AHR. Accordingly, we propose that prolonged induction of AHR activity through inhibition of CYP1 disturbs feedback regulation of FICZ levels, with potential detrimental consequences.

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“…Mammalian species contain only the CYP1A and 1B subfamilies, and the CYP1C subfamily has only been identified in non-mammilian vertebrates (Goldstone et al, 2007). CYP1D1 was first identified in fish , and recently has been found in cynomolgus monkey (Uno et al, 2011).…”

Section: Cyp1 Evolution and Functionmentioning

confidence: 99%

“…Most notably, the CYP1C subfamily is not present in mammals but has been identified in frogs (Jonsson et al, 2011), birds (Goldstone et al, 2007), and fish (Zanette et al, 2009). There is only one isoform in the CYP1A family in fish and this gene (CYP1A) has the rare nomenclature such that the CYP has not been provided a gene number.…”

Section: Cyp1 Evolution and Functionmentioning

confidence: 99%

“…While key isoforms in the mammalian CYP catalogue are well known and extensively researched, there is a need to investigate non-mammilian CYP function as they can differ from similar isoforms in mammals . Even in the well studied CYP1 family, new CYP1 subfamilies in non-mammals (sea urchin, tunicates, birds) have been discovered with no known function (Goldstone et al, 2007). Even more, the new CYP1D subfamily has been discovered in more mammilian species (Kawai et al, 2010), and still does not have in depth functional knowledge for cynomolgus monkey (Uno et al, 2011) and zebrafish Our work showed the ability of a CE-UV method to quickly identify cofactor consumption in CYP1 reactions.…”

Section: Future Workmentioning

confidence: 99%

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Functional Screening of Cytochrome P450 Activity and Uncoupling by Capillary Electrophoresis

2011

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Abstract:Cytochrome P450s are a super-family of heme containing proteins that are found in all domains of life and are involved in the synthesis and breakdown of steroids, xenobiotics, and pharmaceuticals. Using five heterologously expressed zebrafish (Danio rerio) CYP1s, an assay was developed for CYP activity in order to monitor the consumption of the cofactor NADPH, providing a label-free screening tool to determine function of novel CYP genes. Using wellestablished fluorogenic substrates, NADPH and NADP + were separated by capillary electrophoresis (CE) from stopped CYP1 reactions and measured with UV absorbance detection as a surrogate to assess the rate of substrate metabolism. Product formation was confirmed by fluorometric detection of metabolites, giving rates of enzyme activity which could be compared to the rates of cofactor turn-over measured by CE. 17β-estradiol, four alkoxyresorufin and two coumarin based synthetic fluorogenic CYP substrates were screened for activity with recombinant zebrafish CYP1A, 1B1, 1C2, 1C2 and 1D1. Cofactor consumption was generally much larger than product formation for the majority of substrates and CYP1 isoforms, suggesting that the majority of metabolic events were uncoupled. Large uncoupling was seen in CYP1 when metabolizing estradiol, showing that endogenous compounds can also show severe uncoupling.Reactive oxygen species (ROS), a product of uncoupled events, were detected with 2,7-dichorofluorescein. Attempts for concomitant detection of ROS production and cofactor consumption with CE-UV detection were investigated, however, detection limits for 2,7-dichlorofluorescein were not adequate for detection of hydrogen peroxide production from CYP1 mediated reactions. Future work will be required to develop a single assay to quantitatively measure CYP activity by CE for functional determination of CYPs with unknown function.MSc Thesis -J.G. Harskamp McMaster University -Biology iv Acknowledgements:

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Cytochrome P450 1 Genes in Early Deuterostomes (Tunicates and Sea Urchins) and Vertebrates (Chicken and Frog): Origin and Diversification of the CYP1 Gene Family

Cited by 89 publications

References 73 publications

Functional characterization and expression of molluscan detoxification enzymes and transporters involved in dietary allelochemical resistance

Functional characterization and expression of molluscan detoxification enzymes and transporters involved in dietary allelochemical resistance

Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor

Functional Screening of Cytochrome P450 Activity and Uncoupling by Capillary Electrophoresis

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