Postnatal development of hepatic oxidative, hydrolytic and conjugative drug-metabolizing enzymes in female horses.
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.
Nebbia
Carlo
C
Department of Animal Pathology, Division of Pharmacology and Toxicology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco, Italy. carlo.nebbia@unito.it
Dacasto
Mauro
M
Carletti
Monica
M
D000375:Aging / Q000502:physiology*; D000818:Animals; D002104:Cadmium / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D005260:Female; D006736:Horses; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats
D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D002104:Cadmium; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase