Inhibition of in vitro metabolism of testosterone in human, dog and horse liver microsomes to investigate species differences.

Zielinski, Jana; Mevissen, Meike (2015). Inhibition of in vitro metabolism of testosterone in human, dog and horse liver microsomes to investigate species differences. Toxicology in vitro, 29(3), pp. 468-478. Elsevier 10.1016/j.tiv.2014.12.018

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Testosterone hydroxylation was investigated in human, canine and equine liver microsomes and in human and canine single CYPs. The contribution of the CYP families 1, 2 and 3 was studied using chemical inhibitors. Testosterone metabolites were analyzed by HPLC. The metabolites androstenedione, 6β- and 11β-hydroxytestosterone were found in microsomes of all species, but the pattern of metabolites varied within species. Androstenedione was more prominent in the animal species, and an increase over time was seen in equines. Testosterone hydroxylation was predominantly catalyzed by the CYP3A subfamily in all three species. While CYP2C9 did not metabolise testosterone, the canine ortholog CYP2C21 produced androstenedione. Quercetin significantly inhibited 6β- and 11β-hydroxytestosterone in all species investigated, suggesting that CYP2C8 is involved in testosterone metabolism, whereas sulfaphenazole significantly inhibited the formation of 6β- and 11β-hydroxytestosterone in human microsomes, at 60min in equine microsomes, but not in canine microsomes. A contribution of CYP2B6 in testosterone metabolism was only found in human and equine microsomes. Inhibition of 17β-hydroxysteroid dehydrogenase 2 indicated its involvement in androstenedione formation in humans, increased androstenedione formation was found in equines and no involvement in canines. These findings provide improved understanding of differences in testosterone biotransformation in animal species.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Veterinary Pharmacology and Toxicology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Zielinski, Jana and Mevissen, Meike

Subjects:

600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

0887-2333

Publisher:

Elsevier

Language:

English

Submitter:

Meike Mevissen

Date Deposited:

29 Apr 2015 11:31

Last Modified:

16 Apr 2018 16:35

Publisher DOI:

10.1016/j.tiv.2014.12.018

PubMed ID:

25561246

Uncontrolled Keywords:

Canine, Cytochrome P450, Equine, Microsomes, Species differences, Testosterone

BORIS DOI:

10.7892/boris.67562

URI:

https://boris.unibe.ch/id/eprint/67562

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