Stimulation of mixed-function oxidation of 7-ethoxycoumarin in periportal and pericentral regions of the perfused rat liver by xylitol.
Rates of O-deethylation of 7-ethoxycoumarin by perfused livers from fasted, phenobarbital-treated rats were 3.7 mumol X g-1 X h-1. Approximately 50% of the product was conjugated. When rates of 7-ethoxycoumarin O-deethylation were varied by infusing different concentrations of substrate, a good correlation (r = 0.91) was found between rates of O-deethylation of 7-ethoxycoumarin and fluorescence of 7-hydroxycoumarin detected from the liver surface. Micro-light guides (tip diameter 170 microns) placed on periportal and pericentral regions on the liver surface were used to monitor the conversion of nonfluorescent 7-ethoxycoumarin to fluorescent 7-hydroxycoumarin. The O-deethylation of 7-ethoxycoumarin to 7-hydroxycoumarin increased fluorescence 64% and 28% in pericentral and periportal regions of the liver lobule, respectively. Rates of 7-ethoxycoumarin O-deethylation estimated from these increases in fluorescence were 5.2 mumol X g-1 X h-1 in pericentral and 2.2 mumol X g-1 X h-1 in periportal regions of the liver. During mixed-function oxidation of 7-ethoxycoumarin, the oxidation:reduction state of NADP(H) was similar in both regions of the liver lobule. Xylitol (2 mM) decreased the NADP+/NADPH ratio and stimulated rates of drug metabolism in both regions of the liver lobule. This indicates that conditions exist where the supply of NADPH is an important rate-determining factor for 7-ethoxycoumarin metabolism in both periportal and pericentral regions of the liver lobule.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D003374:Coumarins / Q000378:metabolism; D005260:Female; D005453:Fluorescence; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013012:Sorbitol / Q000494:pharmacology; D014468:Umbelliferones / Q000378:metabolism; D014993:Xylitol / Q000494:pharmacology*
D003374:Coumarins; D014468:Umbelliferones; C017299:7-ethoxycoumarin; D013012:Sorbitol; D009249:NADP; C031477:7-hydroxycoumarin; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D014993:Xylitol