Cytochrome P4501A induction caused by the imidazole derivative Prochloraz in a rainbow trout cell line

Babín, María del Mar; Casado, Susana; Chana, Antonio; Herradón, Bernardo; Segner, Helmut; Tarazona, José; Navas, José M.

doi:10.1016/j.tiv.2005.06.037

Cited by 35 publications

(19 citation statements)

References 6 publications

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“…Azole antifungals cause hepatotoxicity by inducing the expression of liver cytochrome P450 enzymes (CYP1, CYP2, and CYP3 families), which in turn increases the abundance of reactive oxygen species in liver cells, resulting in lipid peroxidation and DNA damage (25). In addition, azole antifungals have the potential to inhibit liver P450 enzymes, interfering in the phase I metabolism of xenobiotics (25)(26)(27)(28). Ketoconazole and itraconazole, but not fluconazole, induced CYP1A1 expression in mice (25), and propiconazole induced CYP2B10, CYP3A11, CYP2C55, and CYP2C65 expression in mice (26), along with the formation of benign and malignant liver tumors.…”

mentioning

confidence: 99%

Azole Affinity of Sterol 14α-Demethylase (CYP51) Enzymes from Candida albicans and Homo sapiens

Warrilow

Parker

Kelly

et al. 2013

Antimicrob Agents Chemother

132

115

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Candida albicans CYP51 (CaCYP51) (Erg11), full-length Homo sapiens CYP51 (HsCYP51), and truncated ⌬60HsCYP51 were expressed in Escherichia coli and purified to homogeneity. CaCYP51 and both HsCYP51 enzymes bound lanosterol (K s , 14 to 18 M) and catalyzed the 14␣-demethylation of lanosterol using Homo sapiens cytochrome P450 reductase and NADPH as redox partners. Both HsCYP51 enzymes bound clotrimazole, itraconazole, and ketoconazole tightly (dissociation constants [K d s], 42 to 131 nM) but bound fluconazole (K d , ϳ30,500 nM) and voriconazole (K d , ϳ2,300 nM) weakly, whereas CaCYP51 bound all five medical azole drugs tightly (K d s, 10 to 56 nM). Selectivity for CaCYP51 over HsCYP51 ranged from 2-fold (clotrimazole) to 540-fold (fluconazole) among the medical azoles. In contrast, selectivity for CaCYP51 over ⌬60HsCYP51 with agricultural azoles ranged from 3-fold (tebuconazole) to 9-fold (propiconazole). Prothioconazole bound extremely weakly to CaCYP51 and ⌬60HsCYP51, producing atypical type I UV-visible difference spectra (K d s, 6,100 and 910 nM, respectively), indicating that binding was not accomplished through direct coordination with the heme ferric ion. Prothioconazole-desthio (the intracellular derivative of prothioconazole) bound tightly to both CaCYP51 and ⌬60HsCYP51 (K d , ϳ40 nM). These differences in binding affinities were reflected in the observed 50% inhibitory concentration (IC 50 ) values, which were 9-to 2,000-fold higher for ⌬60HsCYP51 than for CaCYP51, with the exception of tebuconazole, which strongly inhibited both CYP51 enzymes. In contrast, prothioconazole weakly inhibited CaCYP51 (IC 50 , ϳ150 M) and did not significantly inhibit ⌬60HsCYP51. Sterol 14␣-demethylase (CYP51) is an ancestral activity of the cytochrome P450 superfamily and is required for ergosterol biosynthesis in fungi and cholesterol biosynthesis in mammals (1). Fungal CYP51 (Erg11) is the main target for therapeutic azole antifungal drugs and agricultural azole fungicides. This has led to the development of azole inhibitors that are selective for the fungal CYP51 enzyme over the human homolog and are commonly used to treat fungal infections, including those caused by Candida albicans and Aspergillus fumigatus (2-4). Agricultural azoles, however, were developed primarily for selectivity against the fungal CYP51 over the plant homolog. The mode of action of azole antifungals involves the nucleophilic nitrogen of the azole heterocyclic ring directly coordinating as the sixth ligand of the heme ferric ion and the azole drug side chains interacting with the CYP51 polypeptide structure (5).Many yeasts and fungi that are causative agents of clinical infections, such as Candida species and Aspergillus species, are also present in the general environment and are exposed to the selective pressure of agricultural azoles in the field. This has led to concerns that azole-resistant strains of yeasts and fungi responsible for clinical infections are emerging due to the use of agricultural azole fungicides on crops raising azole tole...

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confidence: 99%

Azole Affinity of Sterol 14α-Demethylase (CYP51) Enzymes from Candida albicans and Homo sapiens

Warrilow

Parker

Kelly

et al. 2013

Antimicrob Agents Chemother

132

115

View full text Add to dashboard Cite

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“…On the other hand, prochloraz showed some significant effects on adipose P450s. Prochloraz has been shown to cause CYP1A induction in a rainbow trout cell line (Babín et al, 2005) and to have a mixed induction profile close to that of phenobarbital in rat liver enzymes (Needham et al, 1992). In human hepatocytes, we found that PRO is indeed a CYP2B6 inducer, but mostly a significant CYP1A1/2 inducer.…”

Section: Ellero Et Almentioning

confidence: 56%

Xenobiotic-Metabolizing Cytochromes P450 in Human White Adipose Tissue: Expression and Induction

Ellero

Chakhtoura²,

Barreau³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Lipophilic pollutants can accumulate in human white adipose tissue (WAT), and the consequences of this accumulation are still poorly understood. Cytochromes P450 (P450s) have recently been found in rat WAT and shown to be inducible through mechanisms similar to those in the liver. The aim of our study was to describe the cytochrome P450 pattern and their induction mechanisms in human WAT. Explants of subcutaneous and visceral WAT and primary culture of subcutaneous adipocytes were used as WAT models, and liver biopsies and primary culture of hepatocytes were used as liver models to characterize P450 expression in both tissues. The WAT and liver models were then treated with typical P450 inducers (rifampicin, phenobarbital, and 2,3,7,8-tetrachlorodibenzo-p-dioxin) and lipophilic pollutants (lindane, prochloraz, and chlorpyrifos), and the effects on P450 expression were studied. P450 expression was considerably lower in WAT than in the liver, except for CYP1B1 and CYP2U1, which were the most highly expressed adipose P450s in all individuals. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and prochloraz induced CYP1A1 and CYP1B1 expression in both tissues. The aryl hydrocarbon receptor was also present in WAT. In contrast, neither phenobarbital nor rifampicin treatment induced CYP2 or CYP3 mRNA in WAT, and constitutive androstane receptor and pregnane X receptor were almost undetectable. These results suggest that the mechanisms by which P450s of family 1 are regulated in the liver are also functional in human WAT, but those regulating CYP2 and CYP3 expression are not.

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“…These two compounds, while both acting as aromatase inhibitors, have markedly different effects on steroid hormone catabolism, because prochloraz also is an AhR ligand and hence is known to induce the steroid catabolic CYP1A enzymes in rainbow trout [33,34]. In addition, prochloraz is a potent inhibitor of the CYP3A-mediated steroid hydroxylation [33].…”

Section: Synthesismentioning

confidence: 99%

“…Ligand-bound AhR exerts an estrogenic effect via two distinct mechanisms, the stimulation of E2 production through the activation of Cyp19 gene expression with cooperation of steroidogenic factor (SF)-1 and the activation of empty ER by AhR in ovarian granulosa cells in mice [31]. Fadrozole is thought to be a selective aromatase CYP19 inhibitor [32], whereas prochloraz also is an AhR agonist [33,34], which results in induction of CYP1A genes that can interfere with steroid hormone catabolism in fish.…”

mentioning

confidence: 99%

Species extrapolation for the 21st century

Celander

Goldstone

Denslow

et al. 2010

Enviro Toxic and Chemistry

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Safety factors are used in ecological risk assessments to extrapolate from the toxic responses of laboratory test species to all species representing that group in the environment. More accurate extrapolation of species responses is important. Advances in understanding the mechanistic basis for toxicological responses and identifying molecular response pathways can provide a basis for extrapolation across species and, in part, an explanation for the variability in whole organism responses to toxicants. We highlight potential short- and medium-term development goals to meet our long-term aspiration of truly predictive in silico extrapolation across wildlife species' response to toxicants. A conceptual approach for considering cross-species extrapolation is presented. Critical information is required to establish evidence-based species extrapolation, including identification of critical molecular pathways and regulatory networks that are linked to the biological mode of action and species' homologies. A case study is presented that examines steroidogenesis inhibition in fish after exposure to fadrozole or prochloraz. Similar effects for each compound among fathead minnow, medaka, and zebrafish were attributed to similar inhibitor pharmacokinetic/pharmacodynamic distributions and sequences of cytochrome P45019A1/2 (CYP19A1/2). Rapid advances in homology modeling allow the prediction of interactions of chemicals with enzymes, for example, CYP19 aromatase, which would eventually allow a prediction of potential aromatase toxicity of new compounds across a range of species. Eventually, predictive models will be developed to extrapolate across species, although substantial research is still required. Knowledge gaps requiring research include defining differences in life histories (e.g., reproductive strategies), understanding tissue-specific gene expression, and defining the role of metabolism on toxic responses and how these collectively affect the power of interspecies extrapolation methods.

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Cytochrome P4501A induction caused by the imidazole derivative Prochloraz in a rainbow trout cell line

Cited by 35 publications

References 6 publications

Azole Affinity of Sterol 14α-Demethylase (CYP51) Enzymes from Candida albicans and Homo sapiens

Azole Affinity of Sterol 14α-Demethylase (CYP51) Enzymes from Candida albicans and Homo sapiens

Xenobiotic-Metabolizing Cytochromes P450 in Human White Adipose Tissue: Expression and Induction

Species extrapolation for the 21st century

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