Metabolism of a novel side chain modified Delta8(14)-15-ketosterol, a potential cholesterol lowering drug: 28-hydroxylation by CYP27A1.
The synthetic inhibitors of sterol biosynthesis, 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one and 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one, are of interest as potential cholesterol lowering drugs. Rapid metabolism of synthetic 15-ketosterols may lead to a decrease, or loss, of their potency to affect lipid metabolism. 3beta-Hydroxy-5alpha-cholest-8(14)-en-15-one is reported to be rapidly side chain oxygenated by rat liver mitochondria. In an attempt to reduce this metabolism, the novel side chain modified 15-ketosterol 3beta-Hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one was synthesized. We have examined the metabolism by recombinant human CYP27A1 of this novel side chain modified 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one and compared the rate of metabolism with that of the previously described 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. Both sterols were found to be efficiently metabolized by recombinant human CYP27A1. None of the two 15-ketosterols was significantly metabolized by microsomal 7alpha-hydroxylation. Interestingly, CYP27A1-mediated product formation was much lower with the side chain modified 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one than with the previously described 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one. A surprising finding was that this novel side chain modified sterol was metabolized mainly in the C-28 position by CYP27A1. The data on 28-hydroxylation by human CYP27A1 provide new insights on the catalytic properties and substrate specificity of this enzyme. The finding that 3beta-hydroxy-24S-methyl-5alpha-cholesta-8(14),22-dien-15-one with a modified side chain is metabolized at a dramatically slower rate than the previously described 15-ketosterol with unmodified side chain may be important for future development of synthetic cholesterol lowering sterols.
Pettersson
Hanna
H
Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Uppsala, Sweden.
Norlin
Maria
M
Andersson
Ulla
U
Pikuleva
Irina
I
Björkhem
Ingemar
I
Misharin
Alexander Yu
AY
Wikvall
Kjell
K
D000924:Anticholesteremic Agents / Q000378:metabolism*; D002460:Cell Line; D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism*; D002783:Cholestenones / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004987:Ethers / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
C531953:3-hydroxy-24-methylcholesta-8(14),22-dien-15-one; D000924:Anticholesteremic Agents; D002783:Cholestenones; D004987:Ethers; D011994:Recombinant Proteins; D053493:Cholestanetriol 26-Monooxygenase