Journal article
Acetaminophen UDP-glucuronosyltransferase in ferrets: species and gender differences, and sequence analysis of ferret UGT1A6
Journal of veterinary pharmacology and therapeutics, Vol.24(6), pp.415-422
12/2001
Handle:
https://hdl.handle.net/2376/116704
PMID: 11903872
Abstract
The principal objective of this study was to determine whether ferrets glucuronidate acetaminophen more slowly compared with other species, and if so investigate the molecular basis for the difference. Acetaminophen-UDP-glucuronosyltransferase (UGT) activities were measured using hepatic microsomes from eight ferrets, four humans, four cats, four dogs, rat, mouse, cow, horse, monkey, pig and rabbit. Gender differences between male and female ferret livers were explored using enzyme kinetic analysis. Immunoblotting of microsomal proteins was also performed using UGT-specific antibodies. Finally, the exon 1 region of UGT1A6, a major acetaminophen-UGT, was sequenced. Glucuronidation of acetaminophen was relatively slow in ferret livers compared with livers from all other species except cat. Gender differences were also apparent, with intrinsic clearance (Vmax/Km) values significantly higher in male compared with female ferret livers. Furthermore, Vmax values correlated with densitometric measurements of two protein bands identified with a UGT1A subfamily-specific antibody. No deleterious mutations were identified in the exon 1 or flanking regions of the ferret UGT1A6 gene. In conclusion, like cats, ferret livers glucuronidate acetaminophen relatively slowly. However, unlike cats, in which UGT1A6 is encoded by a pseudogene and dysfunctional, there are no defects in the ferret UGT1A6 gene which could account for the low activity.
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Details
- Title
- Acetaminophen UDP-glucuronosyltransferase in ferrets: species and gender differences, and sequence analysis of ferret UGT1A6
- Creators
- M H Court - Laboratory of Comparative Pharmacogenetics, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111,USA. mcourt01@emerald.tufts.edu
- Publication Details
- Journal of veterinary pharmacology and therapeutics, Vol.24(6), pp.415-422
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- England
- Grant note
- R01-GM-61834 / NIGMS NIH HHS K01-RR-00104 / NCRR NIH HHS
- Identifiers
- 99900548576901842
- Language
- English
- Resource Type
- Journal article