Glucuronidation, oxidative metabolism, and bioactivation of enterolactone in rhesus monkeys.
Enterolactone (ENL) and enterodiol (END) are mammalian lignans derived from the plant lignans matairesionol (MAT), secoisolariciresinol (SECO), and other dietary precursors. ENL was found to undergo extensive glucuronidation with rhesus liver microsomes to form O-glucuronides at both phenolic hydroxy groups. In addition to glucuronidation, ENL was found to be a good substrate for oxidative metabolism. The major products had a m/z of 313 or 295 by LC-MS analysis in negative ion mode and were determined to be products of monohydroxylation of ENL. The m/z 295 products were the result of a dehydration of the m/z 313 in the MS source. Addition of N-acetylcysteine (NAC) to the NADPH incubations resulted in a decrease of at least 2 major monohydroxylated products and the formation of a major and several minor new products with a m/z of 474. The major adduct was isolated, purified for NMR, and confirmed to be the NAC adduct of the ENL catechol. Incubations of ENL with liver microsomes containing UDPGA, NADPH, and NAC resulted in the formation of ENL-glucuronides; no NAC adducts were detected by LC-MS. Incubations of ENL with human and rhesus hepatocytes resulted in several metabolites. The major metabolites in hepatocytes were the glucuronic acid conjugates; minor amounts of the sulfate conjugate(s) and monohydroxylated products were also detected by LC-MS. Glutathione or other thiol adducts were not detected in hepatocytes. Conclusion. The high efficiency and specificity for the glucuronidation of ENL decrease its potential toxicity via CYP450 bioactivation.
Dean
Brian
B
Department of Drug Metabolism, Merck & Co., Inc., Rahway, NJ, USA. Brian_Dean@Merck.com
Chang
Steve
S
Doss
George A
GA
King
Christopher
C
Thomas
Paul E
PE
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D017705:Lignans / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010084:Oxidation-Reduction
D017705:Lignans; D015107:4-Butyrolactone; D000111:Acetylcysteine; C029497:2,3-bis(3'-hydroxybenzyl)butyrolactone