Selective nitros(yl)ation induced in vivo by a nitric oxide-donating cyclooxygenase-2 inhibitor: a NObonomic analysis.
Nitric oxide (NO) enhances anti-inflammatory drug action. Through a metabonomics approach termed "NObonomics," the effects of a prototypic NO donor (organic nitrate)-cyclooxygenase-2 inhibitor hybrid (NO-coxib), NMI-1093, on the NO metabolite status of the circulation and major organs have been profiled in vivo in the rat. An oral anti-inflammatory NMI-1093 bolus elicited acute tissue-, time-, and dose-dependent changes in oxidative and nitroso/nitrosyl NO metabolites. Gastric N-nitrosation and hepatic S-nitrosation and heme nitrosylation emerged as sensitive indices of this NO-coxib's metabolism. Acute NMI-1093-induced nitros(yl)ation correlated positively as a function of nitrate plus nitrite formation across all organs examined, suggesting a unifying in vivo mechanism consequent to NMI-1093 biotransformation that links oxidative and nitros(yl)ative routes of NO chemical biology and thereby may support downstream NO signaling. NMI-1093 depressed erythrocyte nitros(yl)ation, likely by inhibiting cellular carbonic anhydrase and shifting the intracellular balance between nitrogen oxides and carbonates. Glutathione-S-transferase or cytochrome P450 inhibitors also attenuated NMI-1093's NO metabolism in a compartment-selective fashion. Although not itself a NO donor, the des-nitro coxib analog of NMI-1093 influenced basal NO metabolite profiles, implicating a cyclooxygenase-NO synthase interaction in physiological NO regulation. By detailing the global NO metrics of a unique coxib bearing a popular NO-donor pharmacophore (i.e., a nitrate moiety) and defining some critical mechanistic determinants, this study demonstrates how NObonomics can serve as valuable tool in helping elucidate NO systems biology and the effect of NO-donor and non-NO-donating therapeutics thereon.
Dhawan
Vijay
V
NitroMed, Inc., 125 Spring Street, Lexington, MA 02421-7801, USA.
Schwalb
David J
DJ
Shumway
Matthew J
MJ
Warren
Michael C
MC
Wexler
Roseanne S
RS
Zemtseva
Irina S
IS
Zifcak
Brian M
BM
Janero
David R
DR
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000201:enzymology; D005753:Gastric Mucosa / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism*; D010080:Oxazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; C507930:NMI-1093; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; C507931:OH-valdecoxib; D010080:Oxazoles; D013449:Sulfonamides; D009569:Nitric Oxide; D006418:Heme; D002256:Carbonic Anhydrases