Hostname: page-component-848d4c4894-x5gtn Total loading time: 0 Render date: 2024-05-18T14:07:31.465Z Has data issue: false hasContentIssue false
  • English
  • Français

Comparison of three fluorescent CYP3A substrates in two vertebrate models: pig and Atlantic salmon

Published online by Cambridge University Press:  11 November 2011

V. Zlabek  and
G. Zamaratskaia
V. Zlabek*
Affiliation:
Department of Food Science, BioCenter, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, University of South Bohemia in Ceske Budejovice, Zatisi 728/II, 389 25 Vodnany, Czech Republic
G. Zamaratskaia
Affiliation:
Department of Food Science, BioCenter, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden
*
†E-mail: vzlabek@frov.jcu
Get access

Abstract

We investigated in vitro inhibitory effects of ketoconazole (KTZ) on cytochrome P450 activity in microsomes from pigs and Atlantic salmon. The following enzymatic reactions were studied: 7-benzyloxyresorufin and 7-ethoxyresorufin O-dealkylation (BROD and EROD, respectively), 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylation (BFCOD) and 7-benzyloxyquinoline O-debenzylation (BQOD). KTZ was a potent non-competitive inhibitor of BROD and BQOD in the microsomes from pigs, whereas in the microsomes from Atlantic salmon, these reactions were competitively inhibited by KTZ. BFCOD activity was inhibited by KTZ in a non-competitive manner in both species. KTZ non-competitively inhibited EROD in Atlantic salmon, but not in porcine microsomes. The activity of BROD and BQOD was higher in male than that in female pigs, but the activity of BFCOD showed no sex-related differences.

Keywords

ketoconazole7-ethoxyresorufin7-benzyloxyresorufin7-benzyloxy-4-trifluoromethylcoumarin7-benzyloxyquinoline
Type
Full Paper
Information
animal , Volume 6 , Issue 4 , April 2012 , pp. 633 - 640
Copyright
Copyright © The Animal Consortium 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abadie-Viollon, C, Martin, H, Blanchard, N, Pekthong, D, Bachellier, P, Mantion, G, Heyd, B, Schuler, F, Coassolo, P, Alexandre, E, Richert, L 2010. Follow-up to the pre-validation of a harmonised protocol for assessment of CYP induction responses in freshly isolated and cryopreserved human hepatocytes with respect to culture format, treatment, positive reference inducers and incubation conditions. Toxicology in Vitro 24, 346–356.CrossRefGoogle Scholar
Appiah-Opong, R, Commandeur, JNM, van Vugt-Lussenburg, B, Vermeulen, NPE 2007. Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products. Toxicology 235, 83–91.Google Scholar
Beijer, K, Abrahamson, A, Brunström, B, Brandt, I 2010. CYP1A inhibition in fish gill filaments: a novel assay applied on pharmaceuticals and other chemicals. Aquatic Toxicology 96, 145–150.CrossRefGoogle ScholarPubMed
Burke, MD, Thompson, S, Weaver, RJ, Wolf, CR, Mayers, RT 1994. Cytochrome P450 specificities of alkoxyresorufin O-dealkylation in human and rat liver. Biochemistry and Pharmacology 48, 923–936.CrossRefGoogle ScholarPubMed
Chirulli, V, Longo, V, Marini, S, Mazzaccaro, A, Fiorio, R, Gervasi, PG 2005. CAR and PXR expression and inducibility of CYP2B and CYP3A activities in rat and rabbit lungs. Life Sciences 76, 2535–2546.Google Scholar
Christen, V, Oggier, DM, Fent, K 2009. A microtiter-plate-based cytochrome P450 3A activity assay in fish cell lines. Environmental Toxicology and Chemistry 28, 2632–2638.CrossRefGoogle ScholarPubMed
Di Mattina, M, Maronian, N, Ashby, H, Loriaux, DL, Albertson, BD 1988. Ketoconazole inhibits multiple steroidogenic enzymes involved in androgen biosynthesis in the human ovary. Fertility and Sterility 49, 62–65.CrossRefGoogle ScholarPubMed
Dresser, GK, Spence, JD, Bailey, DG 2000. Pharmacokinetic–pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clinical Pharmacokinetics 38, 41–57.CrossRefGoogle ScholarPubMed
Easterbrook, J, Lu, C, Sakai, Y, Li, AP 2001. Effects of organic solvents on the activities of cytochrome P450 isoforms, UDP-dependent glucuronyl transferase, and phenol sulfotransferase in human hepatocytes. Drug Metabolism and Disposition 29, 141–144.Google Scholar
Förlin, L, Celander, M 1993. Induction of cytochrome P450 1A in teleosts: environmental monitoring in Swedish fresh, brackish and marine waters. Aquatic Toxicology 26, 41–56.Google Scholar
Gillberg, M, Skaanild, MT, Friis, C 2006. Regulation of gender-dependent CYP2A expression in pigs: involvement of androgens and CAR. Basic & Clinical Pharmacology & Toxicology 98, 480–487.CrossRefGoogle ScholarPubMed
Greenblatt, DJ, Venkatakrishnan, K, Harmatz, JS, Parent, SJ, von Moltke, LL 2010. Sources of variability in ketoconazole inhibition of human cytochrome P450 3A in vitro. Xenobiotica 40, 713–720.CrossRefGoogle ScholarPubMed
Hagemeyer, CE, Bürck, C, Schwab, R, Knoth, R, Meyer, RP 2010. 7-Benzyloxyresorufin-O-dealkylase activity as a marker for measuring cytochrome P450 CYP3A induction in mouse liver. Analytical Biochemistry 398, 104–111.CrossRefGoogle ScholarPubMed
Hasselberg, L, Grøsvik, BE, Goksøyr, A, Celander, MC 2005. Interactions between xenoestrogens and ketoconazole on hepatic CYP1A and CYP3A, in juvenile Atlantic cod (Gadus morhua). Comparative Hepatology 4, 2. doi:10.1186/1476-5926-4-2.CrossRefGoogle ScholarPubMed
Havelkova, M, Randak, T, Zlabek, V, Krijt, J, Kroupova, H, Pulkrabova, J, Svobodova, Z 2007. Biochemical markers for assessing aquatic contamination. Sensors 7, 2599–2611.Google Scholar
Hegelund, T, Ottosson, K, Rådinger, M, Tomberg, P, Celander, MC 2004. Effects of the antifungal imidazole ketoconazole on CYP1A and CYP3A in rainbow trout and killifish. Environmental Toxicology and Chemistry 23, 1326–1334.Google Scholar
Hickman, D, Wang, J, Wang, Y, Unadkat, JD 1998. Evaluation of the selectivity of in vitro probes and suitability of organic solvents for the measurement of human cytochrome P450 monooxygenase activities. Drug Metabolism and Disposition 26, 207–215.Google ScholarPubMed
Hosomi, H, Akai, S, Minami, K, Yoshikawa, Y, Fukami, T, Nakajima, M, Yokoi, T 2010. An in vitro drug-induced hepatotoxicity screening system using CYP3A4-expressing and gamma-glutamylcysteine synthetase knockdown cells. Toxicology in Vitro 24, 1032–1038.CrossRefGoogle Scholar
Kojima, M, Sekimoto, M, Degawa, M 2008. A novel gender-related difference in the constitutive expression of hepatic cytochrome P4501A subfamily enzymes in Meishan pigs. Biochemical Pharmacology 75, 1076–1082.CrossRefGoogle ScholarPubMed
Kullman, SW, Kashiwada, S, Hinton, DE 2004. Analysis of medaka cytochrome P450 3A homotropic and heterotropic cooperativity. Marine Environmental Research 58, 469–473.Google Scholar
Lamb, DC, Kelly, DE, Waterman, MR, Stromstedt, M, Rozman, D, Kelly, SL 1999. Characteristics of the heterologously expressed human lanosterol 14α-demethylase (other names: P45014DM, CYP51, P45051) and inhibition of the purified human and Candida albicans CYP51 with azole antifungal agents. Yeast 15, 755–763.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
Nannelli, A, Chirulli, V, Longo, V, Gervasi, PG 2008. Expression and induction by rifampicin of CAR- and PXR-regulated CYP2B and CYP3A in liver, kidney and airways of pig. Toxicology 252, 105–112.CrossRefGoogle ScholarPubMed
Puccinelli, E, Gervasi, PG, Longo, V 2011. Xenobiotic metabolizing cytochrome P450 in pig, a promising animal model. Current Drug Metabolism 12, 507–525.CrossRefGoogle ScholarPubMed
Price, RJ, Giddings, AM, Scott, MP, Walters, DG, Capen, CC, Osimitz, TG, Lake, BG 2008. Effect of Pyrethrins on cytochrome P450 forms in cultured rat and human hepatocytes. Toxicology 243, 84–95.CrossRefGoogle ScholarPubMed
Rasmussen, M, Ekstrand, B, Zamaratskaia, G 2011. Comparison of cytochrome P450 concentrations and metabolic activities in porcine hepatic microsomes prepared with two different methods. Toxicology in Vitro 25, 343–346.Google Scholar
Renwick, AB, Surry, D, Price, RJ, Lake, BG, Evans, DC 2000. Metabolism of 7-benzyloxy-4-trifluoromethylcoumarin by human hepatic cytochrome P450 isoforms. Xenobiotica 30, 955–969.Google Scholar
Schlenk, D, Celander, M, Gallagher, EP, George, S, James, M, Kullman, SW, Van den Hurk, P, Willett, K 2008. Biotransformation in fishes. In The Toxicology of fishes (ed. RT Di Giulio and DE Hinton), pp. 154–205. CRC Press, Boca Raton, FL, USA.Google Scholar
Skaanild, MT, Friis, C 1999. Cytochrome P450 sex differences in minipigs and conventional pigs. Pharmacology & Toxicology 85, 174–180.CrossRefGoogle ScholarPubMed
Smith, EM, Wilson, JY 2010. Assessment of cytochrome P450 fluorometric substrates with rainbow trout and killifish exposed to dexamethasone, pregnenolone-16α-carbonitrile, rifampicin, and β-naphthoflavone. Aquatic Toxicology 97, 324–333.Google Scholar
Stresser, DM, Turner, SD, Blanchard, AP, Miller, VP, Crespi, CL 2002. Cytochrome P450 fluorometric substrates: identification of isoform-selective probes for rat CYP2D2 and human CYP3A4. Drug Metabolism and Disposition 30, 845–852.CrossRefGoogle ScholarPubMed
Van der Oost, R, Beyer, J, Vermeulen, NPE 2003. Fish bioaccumulation and biomarkers in environmental risk assessment: a review. Environmental Toxicology and Pharmacology 13, 57–149.Google Scholar
Venkatakrishnan, K, von Moltke, LL, Greenblatt, DJ 2000. Effects of antifungal agents on oxidative drug metabolism: clinical relevance. Clinical Pharmacokinetics 38, 111–180.Google Scholar
Weber, MM, Wil, A, Adelmann, B, Engelhardt, D 1991. Effect of ketoconazole on human ovarian C17,20-desmolase and aromatase. Journal of Steroid Biochemistry and Molecular Biology 38, 213–218.CrossRefGoogle ScholarPubMed
Zamaratskaia, G, Chen, G, Lundström, K 2006. Effects of sex, weight, diet and hCG administration on levels of skatole and indole in the liver and hepatic activities of cytochromes P4502E1 and P4502A6 in pigs. Meat Science 72, 331–338.Google Scholar
Zamaratskaia, G, Zlabek, V, Chen, G, Madej, A 2009. Modulation of porcine cytochrome P450 enzyme activities by surgical castration and immunocastration. Animal 3, 1124–1132.CrossRefGoogle ScholarPubMed
Zamaratskaia, G, Squires, EJ 2009. Biochemical, nutritional and genetic effects on boar taint in entire male pigs. Animal 3, 1508–1521.Google Scholar
Zamaratskaia, G, Zlabek, V 2009. EROD and MROD as markers of cytochrome P450 1A activities in hepatic microsomes from entire and castrated male pigs. Sensors 9, 2134–2147.CrossRefGoogle ScholarPubMed