In vitro glycosidation potential towards olomoucine-type cyclin-dependent kinase inhibitors in rodent and primate microsomes.
Interspecies differences in glycosidation potential in mammalian tissues represent a factor contributing to ambiguity when endobiotic and/or xenobiotic metabolic pathways are extrapolated from animals to man. Using the TLC/autoradiographic technique, we conducted an in vitro investigation involving mouse, rat, monkey, as well as human liver and kidney microsomes to evaluate their glycoconjugation potential towards (3)H-labeled, purine-derived selective inhibitors of cyclin-dependent kinases such as olomoucine, bohemine, roscovitine, 6-(2-hydroxybenzyl)amino-2-(1-hydroxymethyl-2-methylpropyl)amino-9-isopropylpurine (compound A-4), and 6-(3-hydroxybenzyl)amino-2-[(1(R/S)-hydroxymethyl)propyl]amino-9-isopropylpurine (compound A-5) as aglycones. Principally, this study confirmed the aliphatic hydroxyl group of olomoucine-type inhibitors as a relatively suitable target for glucuronide, glucoside, xyloside, galactoside, and/or N-acetylaminoglucoside conjugation. Of the tissues examined, only the mouse microsomes were able to perform glucosidation and galactosidation reactions with the aglycones. On the other hand, monkey microsomes were superior to the mouse microsomes in a variety of glucuronide conjugates produced with compounds A-4 and A-5.
Cervenková
K
K
Department of Pathological Physiology, Medical Faculty, Palacký University, Hnevotínská 3, CZ-775 15 Olomouc, Czech Republic. vesely@tunw.upol.cz
Belejová
M
M
Chmela
Z
Z
Rypka
M
M
Riegrová
D
D
Michnová
K
K
Michalíková
K
K
Súrová
I
I
Brejcha
A
A
Hanus
J
J
Cerný
B
B
Fuksová
K
K
Havlícek
L
L
Veselý
J
J
D000818:Animals; D002855:Chromatography, Thin Layer; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006027:Glycosides / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D007701:Kinetin; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013045:Species Specificity
D004791:Enzyme Inhibitors; D006027:Glycosides; D011687:Purines; C090046:olomoucine; D018844:Cyclin-Dependent Kinases; D007701:Kinetin