CYP3A in horse intestines

Tydén, Eva; Olsén, Lena; Tallkvist, Jonas; Larsson, Peter; Tjälve, Hans

doi:10.1016/j.taap.2004.05.015

Cited by 21 publications

(33 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It might be that the proximal intestine is the major site of CLR hydroxylation in horses, where CYP3A metabolic activity is highly expressed (Tydén et al, 2004). If intestinal metabolism is not influenced or even is induced by RIF, than the uptake carrier for CLR must be located along the "first-pass" route beyond the place of intestinal biotransformation (i.e., in the basolateral membrane of enterocytes).…”

Section: Discussionmentioning

confidence: 99%

Clarithromycin Is Absorbed by an Intestinal Uptake Mechanism That Is Sensitive to Major Inhibition by Rifampicin: Results of a Short-Term Drug Interaction Study in Foals

Peters¹,

Eggers²,

Oswald³

et al. 2011

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Pulmonary penetration of clarithromycin (CLR) in epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALCs) can be influenced by CYP3A4, by P-glycoprotein, and, according to our hypothesis, by a member of the organic anion-transporting protein (OATP) family, for which rifampicin (RIF) is inhibiting in single doses but inducing after long-term coadministration. To assess the partial inhibitory effect, we measured absorption and pulmonary distribution of CLR after short-term (2.5-day) coadministration of RIF, after which up-regulation is not expected. The drug interaction study was performed with five doses (12-h interval) of CLR (7.5 mg/kg) and RIF (10 mg/kg) in nine healthy foals; horse transporters are very similar in protein sequence and transcriptional regulation to the human analogs. RIF was equally distributed in ELF but reached half the plasma levels in BALCs. The deacetylated metabolite accumulated 1.4-to 6-fold in ELF and 8-to 60-fold in BALCs. CLR did not significantly influence the distribution of RIF. CLR and 14-hydroxyclarithromycin (14OH-CLR) accumulated approximately

show abstract

Section: Discussionmentioning

confidence: 99%

Clarithromycin Is Absorbed by an Intestinal Uptake Mechanism That Is Sensitive to Major Inhibition by Rifampicin: Results of a Short-Term Drug Interaction Study in Foals

Peters¹,

Eggers²,

Oswald³

et al. 2011

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…CYP3A4 is also found in extrahepatic tissues, such as the intestines; however, it is notably absent in other tissues, such as the kidney A second member of this subfamily in humans, CYP3A5, is expressed at much lower levels relative to those of CYP3A4, constituting approximately 2% of total P450 3A subfamily enzymes (Koch et al, 2002). In the horse, Tydén et al (2004) have demonstrated expression of CYP3A enzymes in both the liver and extrahepatic tissues, including the intestine and lungs. In the current study we applied quantitative RT-PCR analysis to compare relative expression levels of the three previously identified members of the P450 3A subfamily in the liver and kidney of the horse.…”

Section: Discussionmentioning

confidence: 99%

Molecular Cloning, Expression, and Initial Characterization of Members of the CYP3A Family in Horses

Knych

McKemie

Stanley³

2010

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The use of performance-enhancing drugs in the horse racing industry combined with the need for more rational approaches in the use of therapeutic agents in equids necessitates additional studies on the spectrum, content, and catalytic activities of hepatic cytochrome P450 monooxygenases in this species. In this study, three cytochrome P450 (P450) monooxygenases in the 3A family were cloned from, sequenced, and expressed in a baculovirus expression system. The proteins were designated CYP3A89, CYP3A96, and CYP3A97. Expression studies produced various results among the three proteins. CYP3A89 appears to undergo post-translational modification, producing a truncated protein, and although metabolically active, CYP3A97 did not have a detectable P450 spectrum. Expression of CYP3A96 produced a full-length, catalytically active protein. CYP3A96 catalyzed testosterone, and nifedipine metabolism was 20-and 10-fold slower, respectively, compared with the human counterpart, CYP3A4. Relative hepatic expression levels of each member of the CYP3A family, determined using quantitative reverse transcription-polymerase chain reaction, varied more than 1000-fold in individual horses. The results demonstrate substantial interspecies variability in metabolism of substrates by members of the CYP3A family in the horse and human and support the need to fully characterize 450-mediated metabolism in equids. These studies provide a framework for screening therapeutically useful drugs and provide a method for determination of metabolites of illegal performance-enhancing drugs without the time and expense of either in vivo studies or obtaining liver samples for in vitro analysis.

show abstract

“…The focus of this review is on hepatic cytochromes P450, but these enzymes are also present in extrahepatic tissues such as kidney [10,11], intestine [12][13][14][15], lung [10,11,13,16,17], kidneys [13], coronary arteries [18], olfactory epithelium [19,20], pancreas [21] and tongue [22].…”

Section: Cytochromes P450mentioning

confidence: 99%

Cytochrome P450 Expression in the Liver of Food-Producing Animals

Ioannides

2006

CDM

View full text Add to dashboard Cite

A number of enzyme systems participate in the metabolism of chemicals, but undoubtedly the most important are the cytochromes P450 (CYP). It is a versatile enzyme system, capable of metabolising structurally diverse chemicals. To achieve this broad substrate specificity it exists as a superfamily of enzymes, each family being characterised by different substrate specificity; families CYP1, CYP2 and CYP3 are responsible for the metabolism of exogenous chemicals. Although our current knowledge of the expression and function of cytochromes P450 in humans and laboratory animals is extensive, little is known about this enzyme system in food-producing animals, despite its dominant role in the metabolism of veterinary drugs, and the crucial role it plays in controlling the levels of drug and other chemical residues in edible tissues and food products that humans consume, a matter of major current concern. Most studies dealing with the expression of cytochromes P450 in food-producing animals utilised substrate probes defined in rats and humans and/or antibodies raised to rat or human antigens. Such an approach can prove misleading as it assumes that orthologue proteins in other animals share the same substrate specificity and, moreover, although antibodies raised to human or rat antigens may recognise epitopes in other species, they do not constitute unequivocal proof that the detected proteins are structurally identical. Despite these drawbacks, there is substantial experimental evidence that CYP1, CYP2 and CYP3 families are expressed in food-producing animals, but their role in the metabolism of veterinary drugs and other xenobiotics has not been addressed.

show abstract

CYP3A in horse intestines

Cited by 21 publications

References 29 publications

Clarithromycin Is Absorbed by an Intestinal Uptake Mechanism That Is Sensitive to Major Inhibition by Rifampicin: Results of a Short-Term Drug Interaction Study in Foals

Clarithromycin Is Absorbed by an Intestinal Uptake Mechanism That Is Sensitive to Major Inhibition by Rifampicin: Results of a Short-Term Drug Interaction Study in Foals

Molecular Cloning, Expression, and Initial Characterization of Members of the CYP3A Family in Horses

Cytochrome P450 Expression in the Liver of Food-Producing Animals

Contact Info

Product

Resources

About