# Defining NAD(P)(H) catabolism
## 3 Non-Ribosylated Catabolites of NAD(P)(H)
To avoid nomenclature confusion, we retain the same numbering for the carboxamide moiety on the oxidized pyridine ring as for nicotinamide with the pyridine nitrogen numbered  
Figure 4: Pyridone catabolites derived from the nicotinamide scaffold. as 1 and the carboxamide at position 3. As such, for all the isomers discussed henceforth, the carboxamide position can be mapped to that of nicotinamide and methyl-nicotinamide. It has been established that in mice, N-Me-NAM, like other arylamines, is oxidized by aldehyde oxidases [98] to generate these methyl pyridones (Figure 4; Table 1) and that this oxidative process can associate with the onset of Type 2 diabetes [99]. Pyridone derivatives of \(N\)-methyl-nicotinamide are major urinary metabolites of nicotinamide in humans and most mammals studied (comprehensively reviewed by [PERSON] in 2018 [100]). Briefly, in humans, the \(N\)-methyl-2-pyridone-5-carboxamide, hence referred to as \(N\)-methyl-3-carboxamide-6-pyridone, (Figures 3 and 4, N-Me-6-PY), is the predominant urinary end-product of NAD\({}^{+}\) degradation to nicotinamide by NAD\({}^{+}\)-consuming enzymes, and nicotinamide surplus. In murine models, the \(N\)-methyl-3-carboxamide-4-pyridone (Figures 3 and 4, \(N\)-Me-4-PY) is the most abundant catabolite [101]. Mammalian aldehyde oxidases (AOX) oxidize \(N\)-methyl-nicotinamide to the N-Me-4-PY and N-Me-6-PY [98]. These metabolites and the less abundant \(N\)-methyl-3-carboxamide-2-pyridone (Figure 4, N-Me-2-PY) have been proposed to be generated from the breakdown of NAD and NADP, rather than excess nicotinamide, although no evidence has been provided to support such a mechanism [101; 102]. Other metabolites of nicotinamide include the less often measured 6-hydroxy-nicotinamide, also known as 6-hydroxy-3-carboxamide pyridine, 6-OH-Nam, or 6-PY (Table 1) (Figure 3), the non-methylated form of Me-6-PY [103]. However, the non-methylated pyridine 2-PY and the 4-PY (Table 1; Figure 4) may also be present but not measured. In mice administered nicotinamide or nicotinic acid, the 4 and 6 isomers of Me-PY (Figure 4) can be readily detected and are most abundant when the nicotinamide dose is in excess compared with that of nicotinic acid (NA), indicating that the mice microbiome can only handle so much nicotinamide before it releases it for use by the host [80]. In humans, Me-6-PY is often a major metabolite observed in urine and serum of subjects administered NAD\({}^{+}\) precursors like nicotinamide [80], NR, and NMN [37; 104]. Interestingly, [PERSON] demonstrated that nicotinamide catabolites can serve as biomarkers to study the pathogenesis of bladder cancer [105]. They revealed that the concentration of \(N\)-Me-NAM was considerably decreased in bladder cancer patients with a concomitant increase in the NAM metabolites such as Me-6-PY. Nicotinamide end-products, as well as nicotinamide itself, are present in human and rat plasma, urine, whole blood, and erythrocytes, and their concentrations are elevated in animals with experimental chronic renal failure [68]. In mice, the plasma concentration of \(N\)-Me-4-PY is higher than that of \(N\)-Me-6-PY. This finding is contrary to that in humans with chronic renal failure where \(N\)-Me-6-PY is the predominant catabolite. Surprisingly, chronic kidney disease (CKD) patients show increased levels of \(N\)-methyl-4-pyridone-carboxamide (Me-4-PY) in addition to that of Me-6-PY [97; 105; 106; 107; 108], although Me-4-PY is not a known product of human AOXs [98; 100]. [PERSON] et al. also demonstrated in rats that NAM end products can accumulate in different tissues and can ultimately lead to multiorgan impairment in the uremic state [71]. Importantly, Me-6-PY was shown to inhibit PARP in vitro and therefore potentially affect DNA repair capacity in CKD patients [109]. For further details on the subject, [PERSON] and [PERSON] provided a comprehensive review of the catabolites of methyl nicotinamide in 2016 [100].