Sulfation of apomorphine by human sulfotransferases: evidence of a major role for the polymorphic phenol sulfotransferase, SULT1A1.

Article Details

Citation

Thomas NL, Coughtrie MW

Sulfation of apomorphine by human sulfotransferases: evidence of a major role for the polymorphic phenol sulfotransferase, SULT1A1.

Xenobiotica. 2003 Nov;33(11):1139-48. doi: 10.1080/00498250310001609192.

PubMed ID
14660177 [ View in PubMed
]
Abstract

1. The relative roles of various members of the human sulfotransferase (SULT) enzyme family in the metabolism of apomorphine, a dopamine receptor antagonist used in the treatment of Parkinson's disease and, more recently, erectile dysfunction, were examined. In humans, sulfation is the major route of metabolism of this drug. 2. Using recombinant SULTs expressed in Escherichia coli, R(--)-apomorphine sulfation was studied using the universal barium precipitation assay in the presence of [35S] 3'-phosphoadenosine 5'-phosphosulfate and SULTs 1A1, 1A2, 1A3, 1B1, 1C2, 1E1 and 2A1. It was shown that SULTs 1A1, 1A2, 1A3 and 1E1 all sulfated apomorphine to varying extents. Low activity with SULT1B1 was only seen at the highest concentration (100 microM) and no activity with SULT1C2 or SULT2A1 was observed. 3. Kinetic analysis using purified recombinant SULTs showed that 1A1, 1A3 and 1E1 all had similar Vmax/Km values, although SULT1E1 had a slightly lower Km at around 1 microM compared with approximately 4 microM for the other SULTs. 4. By correlating apomorphine sulfation (at 10 microM) in a bank of 28 liver cytosols with SULT activity towards 10 microM 4-nitrophenol (SULT1A1) and 0.2 microM 17beta-oestradiol (SULT1E1), a strong correlation with SULT1A1 activity was clearly demonstrated, suggesting this enzyme was primarily responsible for hepatic apomorphine sulfation. 5. These findings were confirmed using immuno-inhibition experiments with antibodies against SULT1A and SULT1E1, which showed preferential inhibition of apomorphine sulfation in human liver cytosol by anti-SULT1A. 6. The results strongly implicate SULT1A1 as the major enzyme responsible for hepatic apomorphine metabolism. As SULT1A1 is subject to a common functional polymorphism, sulfation phenotype may be an important determinant of susceptibility to side-effects of apomorphine and/or efficacy of treatment.

DrugBank Data that Cites this Article

Drugs
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
ApomorphineEstrogen sulfotransferaseProteinHumans
Unknown
Substrate
Details
ApomorphineSulfotransferase 1A1ProteinHumans
Unknown
Substrate
Details
ApomorphineSulfotransferase 1A2ProteinHumans
Unknown
Substrate
Details
ApomorphineSulfotransferase 1A3/1A4ProteinHumans
Unknown
Substrate
Details
ApomorphineSulfotransferase family cytosolic 1B member 1ProteinHumans
Unknown
Substrate
Details