MARC1 Is the Main Contributor to Metabolic Reduction of -Hydroxyurea

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Oct 14

PMID 39397364

Authors

Cathrin Klopp

Xiaomei Zhang

Morgan K Campbell

David Kvaskoff

Michel A Struwe

Curtis R Warren

Besnik Bajrami

Axel J Scheidig

Amanda K Jones

Bernd Clement

Affiliations

Soon will be listed here.

Abstract

-Hydroxyurea has been known since the 1960s as an antiproliferative drug and is used both in oncology and for treatment of hematological disorders such as sickle cell anemia where very high daily doses are administered. It is assumed that the cellular effect of -hydroxyurea is caused by inhibition of ribonucleotide reductase, while alternative mechanisms, e.g., generation of nitric oxide, have also been proposed. Despite its many therapeutic applications, the metabolism of hydroxyurea is largely unexplored. The major elimination pathway of -hydroxyurea is the reduction to urea. Since the mitochondrial amidoxime reducing component (mARC) is known for its -reductive activity, we investigated the reduction of NHU by this enzyme system. This study presents and evidence that this reductive biotransformation is specifically mediated by the mARC1. Inactivation by mARC1 is a possible explanation for the high doses of NHU required for treatment.

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