title: Use of 11alpha-deuterium labeled cortisol as a tracer for assessing reduced 11beta-HSD2 activity in vivo following glycyrrhetinic acid ingestion in a human subject.
abstract: This study describes an oral administration of 5 mg of [1,2,4,19-13C4,11alpha-2H]cortisol (cortisol-13C4,2H1) to a human subject performed on two separate occasions, one with cortisol-13C4,2H1 alone and the other with cortisol-13C4,2H1 plus 130 mg per day of glycyrrhetinic acid for 6 days. The stable isotope methodology employed allowed for the evaluation of the individual in vivo activities of the two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), 11beta-HSD1 and 11beta-HSD2, and to demonstrate the sensitivity of changes in cortisol elimination half-life for detecting inhibition of 11beta-HSD2 activity induced with glycyrrhetinic acid. The kinetic analysis associated with the loss of 11alpha-2H during the conversion of cortisol-13C4,2H1 to cortisone-13C4 by 11beta-HSD2 clearly indicated reduced 11beta-HSD2 activity with glycyrrhetinic acid ingestion, as observed by an increase in the elimination half-life of cortisol-13C4,2H1. The elimination half-life of cortisol-13C4,2H1 provided sensitive in vivo measures of 11beta-HSD2 activity and was more sensitive for detecting changes in renal 11beta-HSD2 activity than the measurement of the urinary ratio of free cortisol and free cortisone (UFF/UFE). The 2H-labeling in the 11alpha-position of cortisol served as an appropriate tracer for assessing the reduced 11beta-HSD2 activity in vivo induced by glycyrrhetinic acid.
authors.affiliation: Department of Medicinal Chemistry and Clinical Pharmacy, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. kasuyay@ps.toyaku.ac.jp
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Kasuya
authors.forename: Akitomo
authors.initials: A
authors.lastname: Yokokawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takashima
authors.forename: Hiromi
authors.initials: H
authors.lastname: Shibasaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Furuta
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D002247:Carbon Isotopes; D003348:Cortisone / Q000097:blood / Q000652:urine; D003903:Deuterium / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D019695:Glycyrrhizic Acid / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000097:blood / Q000652:urine; D007700:Kinetics; D008297:Male; D012016:Reference Values; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D002247:Carbon Isotopes; D004791:Enzyme Inhibitors; D019695:Glycyrrhizic Acid; D003903:Deuterium; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D003348:Cortisone; D006854:Hydrocortisone