Concerted actions of the catechol O-methyltransferase and the cytosolic sulfotransferase SULT1A3 in the metabolism of catecholic drugs.
Catecholic drugs had been reported to be metabolized through conjugation reactions, particularly methylation and sulfation. Whether and how these two Phase II conjugation reactions may occur in a concerted manner, however, remained unclear. The current study was designed to investigate the methylation and/or sulfation of five catecholic drugs. Analysis of the spent media of HepG2 cells metabolically labeled with [(35)S]sulfate in the presence of individual catecholic drugs revealed the presence of two [(35)S]sulfated metabolites for dopamine, epinephrine, isoproterenol, and isoetharine, but only one [(35)S]sulfated metabolite for apomorphine. Further analyses using tropolone, a catechol O-methyltransferase (COMT) inhibitor, indicated that one of the two [(35)S]sulfated metabolites of dopamine, epinephrine, isoproterenol, and isoetharine was a doubly conjugated (methylated and sulfated) product, since its level decreased proportionately with increasing concentrations of tropolone added to the labeling media. Moreover, while the inhibition of methylation resulted in a decrease of the total amount of [(35)S]sulfated metabolites, sulfation appeared to be capable of compensating the suppressed methylation in the metabolism of these four catecholic drugs. A two-stage enzymatic assay showed the sequential methylation and sulfation of dopamine, epinephrine, isoproterenol, and isoetharine mediated by, respectively, the COMT and the cytosolic sulfotransferase SULT1A3. Collectively, the results from the present study implied the concerted actions of the COMT and SULT1A3 in the metabolism of catecholic drugs.
Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614, USA.
Katsuhisa
K
Kurogi
Adnan
A
Alazizi
Ming-Yih
MY
Liu
Yoichi
Y
Sakakibara
Masahito
M
Suiko
Takuya
T
Sugahara
Ming-Cheh
MC
Liu
D015239:Arylsulfotransferase; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008745:Methylation; D012995:Solubility; D015238:Sulfotransferases / Q000378:metabolism*; D013463:Sulfuric Acid Esters / Q000378:metabolism; D014334:Tropolone / Q000494:pharmacology
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D013463:Sulfuric Acid Esters; D014334:Tropolone; D002394:Catechol O-Methyltransferase; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C403170:monoamine-sulfating phenol sulfotransferase