Chemoenzymatic preparation of silybin beta-glucuronides and their biological evaluation.
Chemoenzymatic glucuronidation of the optically pure silybin A (1) using ovine liver glucuronyl transferase afforded three beta-glucuronides of silybin, substituted at phenolic OH groups at the positions C-20 (2), C-7 (3), and C-5 (4) formed in the yields 27, 62.5, and 2.5%, respectively. Using these standards, it was shown that the main silybin conjugate in humans is its 20-beta-D-glucuronate (2), while the C-7 regioisomer (3) was formed in lower proportion. The rate of conjugation of (natural) silybin diastereomers 10S, 11S and 10R, 11R, and therefore also their metabolism in humans is rather different. The radical scavenging activity of 2 is considerably lower than that of its aglycone (1); however, the activity of 3 is higher than in the silybin. These findings corroborate the hypothesis that, at physiological pH, the exclusive target for one-electron oxidation of the silybin molecule is the o-methoxy-phenolic structure at C-19, C-20. This is first pharmacological study using optically pure silybin.
Kren
V
V
Institute of Microbiology, Academy of Sciences of the Czech Republic, Laboratory of Biotransformation, Prague, Czech Republic. kren@biomed.cas.cz
Ulrichová
J
J
Kosina
P
P
Stevenson
D
D
Sedmera
P
P
Prikrylová
V
V
Halada
P
P
Simánek
V
V
D002851:Chromatography, High Pressure Liquid; D016166:Free Radical Scavengers / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D020719:Glucuronides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D012838:Silymarin / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D016166:Free Radical Scavengers; D020719:Glucuronides; D012838:Silymarin; D014453:Glucuronosyltransferase