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In vitro comparison of cytochrome P450-mediated metabolic activities in human, dog, cat, and horse.
Abstract: As domestic animals such as cat, horse, and dog increasingly become the clinical targets for drug discovery programs, the need to understand how these animals metabolize xenobiotics becomes more important. In the present study, substrates and inhibitors that were reported to be selective for particular P450 isozymes were used as probes to study in vitro metabolism in horse, dog, cat, and human liver microsomes. Seven selective catalytic activity markers for cytochrome P450-mediated reactions were measured: phenacetin O-deethylase (P4501A1/2), coumarin 7-hydroxylase (P4502A6), tolbutamide hydroxylase (P4502C8/9), S-mephenytoin 4'-hydroxylase (P4502C19), dextromethorphan O-demethylase (P4502D6), chlorzoxazone 6-hydroxylase (P4502E1), and testosterone 6beta-hydroxylase (P4503A4). Metabolic activity was found in every species with each substrate. Under the conditions of this study, it was observed that no one species was more active for any given substrate. However, rather large interspecies differences were observed. There was no marked sex difference in the way the various species metabolized the different substrates. The effect of selective P450 inhibitors on the various activities was tested with furafylline (P4501A2), mouse monoclonal antibody inhibitory to CYP2A6, sulfaphenazole (P4502C9), tranylcypromine (P4502C19), quinidine (P4502D6), diethyldithiocarbamate (P4502E1), and troleandomycin (P4503A4). In most cases, these inhibitors were effective to varying degrees against the activity seen in horse, dog, and cat liver microsomes. However, even at high concentrations, furafylline did not inhibit phenacetin O-deethylase activity in cat and troleandomycin did not affect testosterone 6beta-hydroxylase activity in horse. Sulfaphenazole was not tested in dog and cat because of the low tolbutamide hydroxylase activity. Overall, these results show that there are also large interspecies differences in the way the selective P450 inhibitors affect the in vitro metabolism of the various substrates in horse, dog, and cat liver microsomes.
Publication Date: 1997-10-09 PubMed ID: 9321515 The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Comparative Study
- Journal Article
Summary
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The research article is about a study that explores the metabolism of xenobiotics in domestic animals and humans using certain markers and inhibitors for cytochrome P450-mediated reactions to understand interspecies differences.
Objective of Research
The primary objective of the research is to study the metabolism of xenobiotics, substances foreign to a living organism, in domestic animals (cat, horse, and dog) which are increasingly becoming clinical targets for drug discovery programs. An understanding of how these animals metabolize these substances will help in creating effective drugs for them.
Methodology
- The research uses substrates and inhibitors that are known to be selective for particular P450 isozymes as probes to study in vitro metabolism in horse, dog, cat, and human liver microsomes.
- Seven selective catalytic activity markers for cytochrome P450-mediated reactions were measured, including phenacetin O-deethylase, coumarin 7-hydroxylase, tolbutamide hydroxylase, S-mephenytoin 4′-hydroxylase, dextromethorphan O-demethylase, chlorzoxazone 6-hydroxylase, and testosterone 6beta-hydroxylase.
- The research also analyzed the effect of selective P450 inhibitors on various activities using furafylline, mouse monoclonal antibody inhibitory to CYP2A6, sulfaphenazole, tranylcypromine, quinidine, diethyldithiocarbamate, and troleandomycin.
Results
- The study found metabolic activity in all species with each substrate, and observed large interspecies differences.
- No significant sex difference was noted in the way the various species metabolized the different substrates.
- For most cases, these inhibitors were effective to varying degrees against the activity seen in horse, dog, and cat liver microsomes. However, furafylline did not inhibit phenacetin O-deethylase activity in cats and troleandomycin did not affect testosterone 6beta-hydroxylase activity in horses. Sulfaphenazole was not tested in dog and cat due to low tolbutamide hydroxylase activity.
Conclusion
The results reveal large interspecies differences in the way the selective P450 inhibitors derive the in vitro metabolism. Understanding these differences is vital for successful drug discovery programs targeting these animals.
Cite This Article
APA
Chauret N, Gauthier A, Martin J, Nicoll-Griffith DA.
(1997).
In vitro comparison of cytochrome P450-mediated metabolic activities in human, dog, cat, and horse.
Drug Metab Dispos, 25(10), 1130-1136.
Publication
Researcher Affiliations
- Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec, Canada.
MeSH Terms
- Adolescent
- Adult
- Animals
- Cats
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Enzyme System / metabolism
- Dogs
- Enzyme Inhibitors / pharmacology
- Horses
- Humans
- In Vitro Techniques
- Microsomes, Liver / drug effects
- Microsomes, Liver / metabolism
- Middle Aged
Citations
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