mARC1 Is the Main Contributor to Metabolic Reduction of N -Hydroxyurea.

Autor: Klopp C; Zoological Institute - Structural Biology, Kiel University 24118, Kiel, Germany.; Pharmaceutical Institute - Medicinal Chemistry, Kiel University 24118, Kiel, Germany., Zhang X; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, United States., Campbell MK; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, United States., Kvaskoff D; Department of Drug Discovery Sciences, Discovery Science Technologies (DK, BB), Boehringer Ingelheim Pharma GmbH & Co. 88400, Biberach an der Riss, Germany., Struwe MA; Zoological Institute - Structural Biology, Kiel University 24118, Kiel, Germany.; Pharmaceutical Institute - Medicinal Chemistry, Kiel University 24118, Kiel, Germany., Warren CR; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, United States., Bajrami B; Department of Drug Discovery Sciences, Discovery Science Technologies (DK, BB), Boehringer Ingelheim Pharma GmbH & Co. 88400, Biberach an der Riss, Germany., Scheidig AJ; Zoological Institute - Structural Biology, Kiel University 24118, Kiel, Germany., Jones AK; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, United States., Clement B; Pharmaceutical Institute - Medicinal Chemistry, Kiel University 24118, Kiel, Germany.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Oct 24; Vol. 67 (20), pp. 18090-18097. Date of Electronic Publication: 2024 Oct 13.
DOI: 10.1021/acs.jmedchem.4c01148
Abstrakt: N -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 N -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 N -hydroxyurea is the reduction to urea. Since the mitochondrial amidoxime reducing component (mARC) is known for its N -reductive activity, we investigated the reduction of NHU by this enzyme system. This study presents in vitro and in vivo 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.
Databáze: MEDLINE
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