Inhibition of CYP3A mRNA and protein expression, and enzymatic activity, by enrofloxacin in chickens.
ABSTRACT This study was to investigate the effect of enrofloxacin (EF) on CYP3A in chicken by using quantitative reverse transcription-polymerase chain reaction and immunodetected. The treated chickens were given 5, 25 and 125 mg/kg of EF while the control chickens were treated with the same volume saline. There was no significant difference between the low dose group and controls in the concentration of hepatic microsome protein and total CYP content, while the middle and high dose EF caused the down regulation. Depression of the CYP3A activity, mRNA and protein were observed in treated chickens, and the inhibition degree was different from each group. It was concluded that EF caused the inhibition of CYP3A both in genetic transcription and protein levels. But the inhibition metabolism still needs further researches.
- [Show abstract] [Hide abstract]
ABSTRACT: Currently, there are no reports on the effects of enrofloxacin (EF), a fluoroquinolone antibiotic, on the cytochrome p450 enzymes in fish, although its use as antimicrobial agent in aquaculture has been put forward. Therefore, the in vivo and in vitro effects of EF on hepatic p450 enzymes of sea bass, a widespread food-producing fish, have been evaluated. Sea bass pretreated with a single dose of EF (3 mg/kg i.p.) or with three daily doses of EF (1 mg/kg i.p.) markedly depressed the microsomal N-demethylation of aminopyrine, erythromycin, the O-deethylation of 7-ethoxycoumarin, ethoxyresorufin and the 6beta-testosterone hydroxylase. In vitro experiments showed that EF at 10 microM inhibited the above-mentioned activities and, in particular, the erythromycin N-demethylase (ERND) and 6beta-testosterone-hydroxylase, likely dependant on a p450 3A isoform. When the nature of ERND inhibition by EF was specifically studied with sea bass liver microsomes, it was found that EF is a potent mechanism-based inhibitor, with K(i) of 3.7 microM and a K(inact) of 0.045 min(-1). An immunoblot analysis with anti p450 3A27 of trout showed that the p450 3A isoform, constitutively expressed in sea bass, is particularly susceptible to inactivation by EF. In vitro experiments with sea bass microsomes have also demonstrated that EF is oxidative deethylated by the p450 system to ciprofloxacin (CF) and that this compound maintains the ability to inactivate the p450 enzymes. The mechanism by which EF or CF inactivate the p450 enzymes has not been studied but an attack of p450 on the cyclopropan ring, present, both in EF and CF structure, with the formation of electrophilic intermediates (i.e. radicals) has been postulated. In conclusion, the EF seems to be a powerful inhibitor of p450s in the sea bass. Therefore, the clinical use of this antibiotic in aquaculture has to be considered with caution.Aquatic Toxicology 02/2003; 62(1):27-33. · 3.73 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: To explore whether CYP3A inhibition by metronidazole is the primary mechanism by which metronidazole interacts with coadministered CYP3A substrates. Literature was accessed using the MEDLINE database (1966-February 2007). Search terms included metronidazole, cytochrome P450, CYP3A4, CYP3A5, drug interactions, and P-glycoprotein. References from pertinent articles, as well as from tertiary sources, were also considered. All articles identified from the data sources that were published in English were evaluated. Case reports and pharmacokinetic evaluations were included. Elevated plasma concentrations and toxicities have been reported for a number of CYP3A substrates including amiodarone, carbamazepine, quinidine, tacrolimus, and cyclosporine when administered with metronidazole. This has led to the widespread belief that metronidazole is a significant inhibitor of CYP3A4. However, 4 pharmacokinetic studies conducted in humans showed that metronidazole did not increase plasma concentrations of the CYP3A substrates midazolam, erythromycin, cyclosporine, and alprazolam, thereby refuting the suggestion that metronidazole is a CYP3A4/5 inhibitor. Drug interactions between metronidazole and certain CYP3A substrates do not appear to result from CYP3A4/5 inhibition by metronidazole. Until any mechanism is identified by which metronidazole alters the disposition of certain CYP3A substrates, drug interactions with this agent should be assessed on a case-by-case basis, taking into account the safety index of the coadministered drug and the availability of equally effective substitutes for either metronidazole or the drug with which it putatively interacts.Annals of Pharmacotherapy 05/2007; 41(4):653-8. · 2.57 Impact Factor
- The Journal of Clinical Pharmacology 04/2009; 49(3):368-9; author reply 370. · 2.84 Impact Factor