Sulphotransferase-dependent dehydration of atropine and scopolamine in guinea pig.
1. Enzymatic dehydration of atropine and scopolamine was studied in guinea pig. 2. The incubation of these alkaloids with guinea pig liver cytosol in the absence of cofactors gave no dehydrated metabolite. However, when atropine and scopolamine were incubated with cytosol supplemented with ATP and sodium sulphate, dehydrated metabolites, apoatropine and aposcopolamine were formed. The formation of these metabolites was confirmed by gas chromatography-mass spectrometry. 3. The reaction required ATP as well as cytosol as the obligatory factors. Deletion of sodium sulphate from the reaction mixture also resulted in a decrease of the activities, although this treatment showed limited effect when the low concentration of atropine was used. Furthermore, dehydroepiandrosterone, an excellent substrate for hydroxysteroid-sulphotransferase, effectively inhibited the in vitro activity of atropine dehydration. 4. Administration of dehydroepiandrosterone to guinea pig followed by atropine treatment caused decreased urinary excretion of apoatropine. 5. These results strongly suggested that the dehydration of atropine and scopolamine takes place via the sulphate conjugate intermediates produced from the sulphotransferase-catalysed reaction. The present finding is the first example of the sulphotransferase-dependent dehydration of a drug, and its generality in drug metabolism is discussed.
Wada
S
S
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Shimizudani
T
T
Yamada
H
H
Oguri
K
K
Yoshimura
H
H
D000818:Animals; D001285:Atropine / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology; D008297:Male; D012601:Scopolamine / Q000378:metabolism*; D015238:Sulfotransferases / Q000378:metabolism*
D003687:Dehydroepiandrosterone; D001285:Atropine; D012601:Scopolamine; D015238:Sulfotransferases; C091209:atropine dehydrase