In vivo production of nitric oxide in rats after administration of hydroxyurea.
The metabolism of nitrovasodilators such as glyceryl trinitrate and nitroprusside provides the active moiety of these drugs (that is, nitric oxide). This process is not limited to the known nitrovasodilators, but also occurs with nitroaromatic antimicrobials. Here we report that the administration of hydroxyurea, an antitumor drug, to rats at pharmacological doses formed detectable nitrosyl hemoglobin, which increased with dose. At higher doses, nitrosyl hemoprotein complexes could also be detected in liver tissue. [15N]hydroxyurea was synthesized and compared with [14N]hydroxyurea. These observations verified that nitric oxide detected as nitrosyl hemoglobin or nitrosyl hemoprotein complexes in rats was the result of the metabolism of hydroxyurea. The time course and dose-dependence of nitric oxide generation were also investigated. Hydroxyurea's antineoplastic activity is caused by its direct action on ribonucleotide reductase, the rate-limiting enzyme in DNA synthesis. Because nitric oxide also inhibits ribonucleotide reductase, this metabolite may supplement this action of hydroxyurea. In addition, the known ability of hydroxyurea to ease the pain of sickle cell anemia patients may be the result of vasodilation by the drug-derived nitric oxide.
Jiang
J
J
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Jordan
S J
SJ
Barr
D P
DP
Gunther
M R
MR
Maeda
H
H
Mason
R P
RP
D000818:Animals; D000986:Antisickling Agents / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D006418:Heme / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006918:Hydroxyurea / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
D000986:Antisickling Agents; D006454:Hemoglobins; C008657:nitrosyl hemoglobin; D009569:Nitric Oxide; D006418:Heme; D006918:Hydroxyurea