In vivo mouse model for analysis of hydroxysteroid (17beta) dehydrogenase 1 inhibitors.
Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) catalyzes the reaction between the low active 17-ketosteroids and the highly active 17beta-hydroxysteroids. In the present study, we have generated transgenic (TG) mice expressing human (h) HSD17B1 under mouse mammary tumor virus (MMTV) promoter (MMTV-hHSD17B1TG mice). The MMTV-hHSD17B1TG mice were used to characterize HSD17B1 enzyme activity and properties of HSD17B1 inhibitor in vivo. Expression of the transgene was detected by enzyme activity and RT-PCR analysis. Increased HSD17B1 activity in the TG mice was detected in vivo by applying estrone as a substrate via an intravenous injection. The developed enzyme activity measurement was then applied to analyze the efficacy of HSD17B1 inhibitor in vivo. The results indicated that the MMTV-hHSD17B1TG mouse model is a valuable novel tool to test human HSD17B1 inhibition by various compounds in vivo. With the potent hHSD17B1 inhibitor compound tested, at highest an 85% and 33% inhibition of the enzyme activity in males and in females, respectively, was observed.
Lamminen
Tarja
T
Department of Physiology, Institute of Biomedicine, FIN-20014 University of Turku, Kiinamyllynkatu 10, Turku, Finland.
Saloniemi
Taija
T
Huhtinen
Kaisa
K
Koskimies
Pasi
P
Messinger
Josef
J
Husen
Bettina
B
Thole
Hubert
H
Poutanen
Matti
M
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D011401:Promoter Regions, Genetic / Q000235:genetics; D019076:Transgenes
D004791:Enzyme Inhibitors; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase