Drug Discov Ther. 2011;5(4):162-175. (DOI: 10.5582/ddt.2011.v5.4.162)

Creatinine and HMH (5-hydroxy-1-methylhydantoin, NZ-419) as intrinsic hydroxyl radical scavengers.

Ienaga K, Yokozawa T


Creatinine (Crn) is one of the main intrinsic hydroxyl radical (•OH) scavengers and an ideal one for healthy or normal mammals, although this fact has not yet become widely accepted. Our results from urinary data estimated that ca. 0.4-0.6% of Crn is used daily to scavenge •OH in normal mammals [ca. 50 μmole and ca. 400 pmole of •OH in healthy subjects and normal rats, respectively]. In human subjects, Crn reacts non-enzymatically with •OH to form creatol (CTL: 5-hydroxycreatinine) and demethylcreatinine (DMC) in a one to one ratio, and CTL partially decomposes to methylguanidine (MG). And so, the scavenged mole of •OH by Crn is nearly equal to their molar total sum (CTL + MG + DMC) or 2 × (CTL + MG). The molar ratio of (scavenged •OH)/Crn in healthy subjects and normal rats are 4.4 and 6.0 mmole/mole, respectively, i.e. almost similar, but in patients with chronic kidney disease (CKD) the ratio increases up to ca. 60 mmole/mole in proportion to the severity of CKD. Since the level of Crn might not be enough to scavenge all •OH, and MG starts accumulating as a uremic toxin, Crn is not really the ideal scavenger. 5-Hydroxy-1-methylhydantoin (HMH, NZ-419), a Crn metabolite, is another antioxidant, having •OH scavenging ability, and has been shown to inhibit the progression of CKD in rats in stead of Crn, if sufficient amounts are given orally.

KEYWORDS: Creatinine, HMH (NZ-419), intrinsic antioxidant, creatol, methylguanidine, demethylcreatinine

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