Applicability of cultured hepatocytes derived from goat, sheep and cattle in comparative drug metabolism studies.
1. Using trimethoprim (TMP), scoparone (SCOP), ethylmorphine (EtM), 1-naphthol (1-N) and phenol red (PhR) as test substrates, biotransformation activities were investigated in cultured hepatocytes from male and female rat, male and female goat, and female sheep and cattle. 2. As compared with rat hepatocytes, the total culture cytochrome P450 content was relatively well maintained in ruminant hepatocytes. In 72 h, it decreased to approximately half the initial content, whereas in rat hepatocytes only 30% was maintained. In ruminant hepatocytes, sulphation of 1-N remained fairly stable, glucuronidation of PhR decreased gradually, and glucuronidation of 1-N increased during the 72-h culture period. 3. Oxidative metabolism of TMP was rapid in goat and sheep hepatocytes, as compared with rat hepatocytes, reflecting species differences in TMP pharmacokinetics in vivo. In contrast with rat hepatocytes, 6-O-demethylation was by far the major pathway of scoparone metabolism in ruminant hepatocytes. The glucuronidation and sulphation activities were similar among the species. 4. In goat liver cells, sex differences in some oxidative biotransformations were observed, females being more active than males. In rat hepatocytes, a reverse sex difference was observed. 5. In conclusion, cultured hepatocytes from agricultural target species appear a useful in vitro model to study comparative metabolism of veterinary drugs and other xenobiotics. Comparing rat and ruminant, sex and species differences and similarities in drug metabolism can be observed that reflect the in vivo situation.
van 't Klooster
G A
GA
Department of Veterinary Basic Sciences, University of Utrecht, The Netherlands.
Woutersen-van Nijnanten
F M
FM
Blaauboer
B J
BJ
Noordhoek
J
J
van Miert
A S
AS
D000818:Animals; D001711:Biotransformation; D002417:Cattle; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003374:Coumarins / Q000378:metabolism / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005036:Ethylmorphine / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006041:Goats; D008099:Liver / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009284:Naphthols / Q000378:metabolism / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D010637:Phenolsulfonphthalein / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D012756:Sheep; D013045:Species Specificity; D013431:Sulfates / Q000378:metabolism; D014295:Trimethoprim / Q000378:metabolism / Q000493:pharmacokinetics; D015262:Xenobiotics / Q000378:metabolism* / Q000493:pharmacokinetics
D003374:Coumarins; D005965:Glucuronates; D009284:Naphthols; D013431:Sulfates; D015262:Xenobiotics; C029350:1-naphthol; D003577:Cytochrome P-450 Enzyme System; D014295:Trimethoprim; C018145:scoparone; D010637:Phenolsulfonphthalein; D005036:Ethylmorphine