# Defining NAD(P)(H) catabolism
## 3 Non-Ribosylated Catabolites of NAD(P)(H)  
Primary catabolites of nicotinic acid and nicotinamide: Nicotinic acid and nicotinamide obtained from dietary sources are used for NAD\({}^{+}\) synthesis, and most of the nicotinamide generated from NAD\({}^{+}\) degradation is salvaged back to NAD\({}^{+}\). However, excess nicotinamide, either released from orally administered NAD\({}^{+}\) supplements (e.g., nicotinamide, NR, or NMN) or not recycled to NAD\({}^{+}\), is subject to three major enzymatic clearance pathways. Nicotinamide is a substrate for microbial eamidases and can be converted to nicotinic acid by the microbiome [78]. In the mammalian gut, nicotinic acid generated from nicotinamide is adsorbed, enters circulation, and is promptly converted to NAD\({}^{+}\)[79; 78]. In the liver, excess nicotinic acid does not enter the NAD\({}^{+}\) Preiss-Handler pathway and is metabolized to nicotinic acid (NUA) by conjugation with glycine [80]. NUA (Table 1) is found in urine and is particularly abundant following nicotinic acid intake [81; 82]. It has been proposed that changes in NUA levels can reveal an important pathogenic transition from metabolic syndrome to diabetes and atherosclerotic cardiovascular disease and thus be a potential marker of metabolic syndrome disease progression [83]. If not converted to nicotinic acid, excess nicotinamide, either from dietary and supplement sources or from NAD\({}^{+}\) degradation, can be oxidized to nicotinamide \(N\)-oxide (Figure 3) by CYP2E1 in the liver [84]. This end-product (Table 1) is found in circulation and as a urinary metabolite [85]. Interestingly, CYP2E1 is an enzyme that participates in the metabolism of other endogenous substrates, including acetone and fatty acids as well as exogenous compounds such as anesthetics, ethanol, nicotine, and acetaminophen. Excess nicotinamide might delay their metabolism. The most common degradation pathway for nicotinamide is methylation. Excess nicotinamide (from supplementation or increased NAD\({}^{+}\) consumption) is often associated with increased plasma, serum, and urinary levels of \(N\)-Me-NAM (Table 1) [31; 80]. [PERSON] et al., demonstrated that excess nicotinamide led to catecholamine degradation in hypertensive mice resulting from the perturbation of the methylation pool and ultimately leading to enhanced levels of nicotinamide, homocysteine, and norepinephrine [77]. The enzyme responsible for the methylation of nicotinamide is now known as nicotinamide \(N\)-methyl transferase (NNMT) [86]. NNMT uses S-adenosylmethionine (SAM) as a co-substrate and methyl donor and generates \(N\)-methyl-nicotinamide (N-Me-NAM) and S-adenosyl prospective (SAH) (Figure 3), which is ultimately converted to homocysteine. Excess NAM and increased levels of \(N\)-Me-NAM have been associated with hyper-homocysteineemia and cardiovascular diseases, although the vasoprotective, anti-inflammatory, and anti-thrombotic roles of \(N\)-Me-NAM have also been documented [87]. More recent work indicates that methyl-nicotinamide might have a beneficial effect on cancer and cancer metastasis [88], while NNMT was shown to protect against oxidative stress-induced endothelial injury [89]. Alternatively, the progression of chronic kidney diseases is associated with a trend toward an increase in methylated catabolites of nicotinamide, whereby NNMT expression induces NAD\({}^{+}\) and methionine metabolism perturbation contributing to renal and hepatic fibrosis [90; 91]. NNMT hyper-activity not only affects NAD\({}^{+}\) and SAM levels but can also redirect epigenomics and epi transcriptomics events [79; 92]. However, a recent publication reported that NR supplementation (1 g/day) is not associated with altered methylation homeostasis in [PERSON]'s disease [93]. Other studies have shown that nicotinamide supplementation resulted in a dose-dependent increase in oxidative stress and 8-hydroxy-2\({}^{\prime}\)-deoxyguanosine (8-OHdG)-positive cells both in the liver and kidneys and correlated with NNMT activity [74].