Postnatal development of hepatic oxidative, hydrolytic and conjugative drug-metabolizing enzymes in female horses.
Abstract: Little is known about the effects of aging on the hepatic drug metabolizing capacity of horses despite the relatively long lifespan characterizing this species. A wide array of cytochrome P450 (CYP)-dependent monooxygenases, carboxylesterases and transferases were assayed in liver microsomes from 50 female horses in an age range between less than 1 year to over 12 years. Rather unexpectedly, both the CYP content and the activity of NADPH cytochrome c reductase rose as a function of age. Accordingly, a general increasing trend was recorded in the rate of the in vitro metabolism of the substrates reported to be related to CYP2B-, CYP2E- or CYP3A, although, as detected by Western immunoblotting, only the levels of proteins recognized by anti-rat CYP3A- and CYP2B antibodies appeared to increase consistently. Also the carboxylesterases and uridindiphosphoglucuronyl-transferase (UGT) activity toward 1-naphthol displayed a similar trend, glutathione S-transferase accepting 3,4-dichloronitrobenzene as a substrate being the only enzyme activity showing an age-related decline. A positive correlation was also found between liver cadmium content and CYP amount as well as the activities of most monooxygenases (except for those related to CYP1A), carboxylesterases, and UGT. While confirming that a number of enzyme activities are less expressed in foals, our results contradict the general view that the drug metabolizing capacity drops in elder individuals. Although several other factors can influence the kinetics of foreign compounds in aged animals, data from this study may provide insight in understanding possible age-related differences in drug efficacy and the response to toxic substances in horses.
Publication Date: 2004-01-24 PubMed ID: 14738905DOI: 10.1016/j.lfs.2003.08.028Google Scholar: Lookup
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- Journal Article
Summary
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This study investigates how age affects the liver’s ability to metabolize drugs in horses, focusing on various enzymes involved in this process. The results indicate that contrary to common belief, the drug metabolizing capacity actually increases with age in horses, highlighting certain enzymes that show this trend.
Methodology
- The study was based on liver microsomes from 50 female horses ranging in age from less than 1 year to over 12 years.
- Researchers measured the activity and content of several cytochrome P450 (CYP)-dependent monooxygenases, carboxylesterases and transferases.
- A variety of tests were carried out, including CYP content, kinetic assays, western immunoblotting, and liver cadmium content assays.
Findings
- The study found an unexpected increase in the level of CYP content and the activity of NADPH cytochrome c reductase with age.
- This led to higher metabolism rates for substrates linked to CYP2B-, CYP2E- or CYP3A enzymes.
- Protein levels increased with age for proteins recognized by anti-rat CYP3A- and CYP2B antibodies.
- Carboxylesterase and UGT activities also showed a rise with advancing age, with only one enzyme activity (glutathione S-transferase accepting 3,4-dichloronitrobenzene as a substrate) showing an age-related decline.
- There was a positive link between liver cadmium content and the amount of CYP, along with the activities of most monooxygenases (except for those related to CYP1A), carboxylesterases, and UGT.
Implications
- The findings challenge the widely accepted notion that drug metabolizing capacity drops in elder individuals. In horses, at least, the opposite seems to be true.
- Foals (young horses) show less expression of a number of enzyme activities, affirming existing knowledge, but the general trend is towards increased activity with age.
- These findings can help to understand possible age-related differences in drug efficacy and responses to toxic substances in horses.
Cite This Article
APA
Nebbia C, Dacasto M, Carletti M.
(2004).
Postnatal development of hepatic oxidative, hydrolytic and conjugative drug-metabolizing enzymes in female horses.
Life Sci, 74(13), 1605-1619.
https://doi.org/10.1016/j.lfs.2003.08.028 Publication
Researcher Affiliations
- Department of Animal Pathology, Division of Pharmacology and Toxicology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco, Italy. carlo.nebbia@unito.it
MeSH Terms
- Aging / physiology
- Animals
- Cadmium / metabolism
- Cytochrome P-450 Enzyme System / metabolism
- Enzyme Induction
- Female
- Horses
- Isoenzymes / metabolism
- Liver / enzymology
- NADPH-Ferrihemoprotein Reductase / metabolism
- Pharmaceutical Preparations / metabolism
- Random Allocation
- Rats
Citations
This article has been cited 1 times.- Gusson F, Carletti M, Albo AG, Dacasto M, Nebbia C. Comparison of hydrolytic and conjugative biotransformation pathways in horse, cattle, pig, broiler chick, rabbit and rat liver subcellullar fractions.. Vet Res Commun 2006 Apr;30(3):271-83.
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