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Hydroxysteroid sulfotransferase and a specific UDP-glucuronosyltransferase are involved in the metabolism of digitoxin in man

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Summary

In vitro experiments were performed with cytosolic and microsomal fractions of human liver specimens in order to investigate which enzyme forms of sulfotransferase (ST) and UDP-glucurosyltransferase (GT) are involved in the metabolism of digitoxin (dt-3) and/or its cleavage products. It was found that the cytosolic STs preferentially react with digitoxigenin (dt-0) whereas microsomal GTs conjugate digitoxigenin-monodigitoxoside (dt-1) and in traces the bisdigitoxoside (dt-2). Dt-3 and dt-0 cannot be glucuronidated. By separation of different sulfotransferases it was found that the hydroxysteroid-ST is responsible for dt-0 and 3-epidigitoxigenin (epi-dt-0) sulfation. The hydroxysteroid-ST could be purified and characterized (apparent Km and Vmax for dt-0 sulfation: approx. 17 μmol/l and 2.7 nmol/min mg protein, respectively). Of various model substrates and endogenous compounds (steroids, bilirubin) none caused a competitive inhibition of the microsomal dt-1 glucuronidation except dt-2 and dt-3. Therefore it can be supposed that a new GT form catalyses this reaction. It is characterized by an extraordinarily high affinity towards dt-1 with Km values ranging between 0.7 and 27 μmol/l.

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Abbreviations

DHEA:

dehydroepiandrosterone

dg-0:

digoxigenin

dg-1:

digoxigenin-monodigitoxoside

dt-0:

digitoxigenin

dt1:

digitoxigenin-monodigitoxoside

dt-2:

digitoxigenin-bisdigitoxoside

dt-3:

digitoxigenin-trisdigitoxoside, digitoxin

epi-dt-0:

3-epi-digitoxigenin

GT:

UDP-glucuronosyltransferase

PAPS:

3′-phosphoadenosine-5′-phosphosulfate

ST:

sulfotransferase

UDPGA:

UDP-glucuronic acid

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Authors and Affiliations

  1. Institute for Legal Medicine, University of Hamburg, Butenfeld 34, W-2000, Hamburg 54, Federal Republic of Germany

    Achim Schmoldt, Ingbert Blömer & Andrea Johannes

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  1. Achim Schmoldt
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  2. Ingbert Blömer
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  3. Andrea Johannes
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Schmoldt, A., Blömer, I. & Johannes, A. Hydroxysteroid sulfotransferase and a specific UDP-glucuronosyltransferase are involved in the metabolism of digitoxin in man. Naunyn-Schmiedeberg's Arch Pharmacol 346, 226–233 (1992). https://doi.org/10.1007/BF00165306

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  • DOI: https://doi.org/10.1007/BF00165306

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