Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells

Nicotinamide (NAM), a form of vitamin B-3, plays essential roles in cell physiology through facilitating NAD(+) redox homeostasis and providing NAD(+) as a substrate to a class of enzymes that catalyze non-redox reactions. These non-redox enzymes include the sirtuin family proteins which deacetylate target proteins while cleaving NAD(+) to yield NAM. Since the finding that NAM exerts feedback inhibition to the sirtuin reactions, NAM has been widely used as an inhibitor in the studies where SIRT1, a key member of sirtuins, may have a role in certain cell physiology. However, once administered to cells, NAM is rapidly converted to NAD(+) and, therefore, the cellular concentration of NAM decreases rapidly while that of NAD(+) increases. The result would be an inhibition of SIRT1 for a limited duration, followed by an increase in the activity. This possibility raises a concern on the validity of the interpretation of the results in the studies that use NAM as a SIRT1 inhibitor. To understand better the effects of cellular administration of NAM, we reviewed published literature in which treatment with NAM was used to inhibit SIRT1 and found that the expected inhibitory effect of NAM was either unreliable or muted in many cases. In addition, studies demonstrated NAM administration stimulates SIRT1 activity and improves the functions of cells and organs. To determine if NAM administration can generate conditions in cells and tissues that are stimulatory to SIRT1, the changes in the cellular levels of NAM and NAD(+) reported in the literature were examined and the factors that are involved in the availability of NAD(+) to SIRT1 were evaluated. We conclude that NAM treatment can hypothetically be stimulatory to SIRT1.