title: 3,4-Dehydrodebrisoquine, a novel debrisoquine metabolite formed from 4-hydroxydebrisoquine that affects the CYP2D6 metabolic ratio.
abstract: Considerable unexplained intersubject variability in the debrisoquine metabolic ratio (urinary debrisoquine/4-hydroxydebrisoquine) exists within individual CYP2D6 genotypes. We speculated that debrisoquine was converted to as yet undisclosed metabolites. Thirteen healthy young volunteers, nine CYP2D6*1 homozygotes [extensive metabolizers (EMs)] and four CYP2D6*4 homozygotes [poor metabolizers (PMs)] took 12.8 mg of debrisoquine hemisulfate by mouth and collected 0- to 8- and 8- to 24-h urines, which were analyzed by gas chromatography-mass spectrometry (GCMS) before and after treatment with beta-glucuronidase. Authentic 3,4-dehydrodebrisoquine was synthesized and characterized by GCMS, liquid chromatography-tandem mass spectrometry, and (1)H NMR. 3,4-Dehydrodebrisoquine is a novel metabolite of debrisoquine excreted variably in 0- to 24-h urine, both in EMs (3.1-27.6% of dose) and PMs (0-2.1% of dose). This metabolite is produced from 4-hydroxydebrisoquine in vitro by human and rat liver microsomes. A previously unstudied CYP2D6*1 homozygote was administered 10.2 mg of 4-hydroxydebrisoquine orally and also excreted 3,4-dehydrodebrisoquine. EMs excreted 6-hydroxydebrisoquine (0-4.8%) and 8-hydroxydebrisoquine (0-1.3%), but these phenolic metabolites were not detected in PM urine. Debrisoquine and 4-hydroxydebrisoquine glucuronides were excreted in a highly genotype-dependent manner. A microsomal activity that probably does not involve cytochrome P450 participates in the further metabolism of 4-hydroxydebrisoquine, which we speculate may also lead to the formation of 1- and 3-hydroxydebrisoquine and their ring-opened products. In conclusion, this study suggests that the traditional metabolic ratio is not a true measure of the debrisoquine 4-hydroxylation capacity of an individual and thus may, in part, explain the wide intragenotype variation in metabolic ratio.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Zhen
authors.forename: Ondrej
authors.initials: O
authors.lastname: Slanar
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Chi
authors.initials: C
authors.lastname: Chen
authors.forename: Josef
authors.initials: J
authors.lastname: Slavík
authors.forename: Kerry L
authors.initials: KL
authors.lastname: McPhail
authors.forename: T Mark
authors.initials: TM
authors.lastname: Zabriskie
authors.forename: Frantisek
authors.initials: F
authors.lastname: Perlík
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
mesh_terms: D000328:Adult; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003647:Debrisoquin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D014644:Genetic Variation; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D006836:Hydro-Lyases / Q000378:metabolism*; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver; D010641:Phenotype
chemical_list: C515157:3,4-dehydrodebrisoquine; D000959:Antihypertensive Agents; D020719:Glucuronides; C012359:4-hydroxydebrisoquin; D019389:Cytochrome P-450 CYP2D6; D006836:Hydro-Lyases; D003647:Debrisoquin