Dimethyl Fumarate vs. Monomethyl Fumarate: Unresolved Pharmacologic Issues.

Dimethyl fumarate (DMF) has established a significant position among therapies for multiple sclerosis and psoriasis and is now being investigated for repurposing to many other non-malignant diseases. Despite decades of preclinical research, some issues about its pharmacology remain unresolved, with ongoing debate over which of the methyl esters of fumarate, whether DMF or monomethyl fumarate (MMF), is the active ingredient. It is generally accepted that DMF undergoes enzymatic hydrolysis to MMF and methanol. However, there is disagreement regarding its exact site, its extent, and the responsible enzyme(s). The enzymatic mechanisms, particularly the roles of carboxylesterases-1 and 2, vary across tissues and species, complicating the translation of in vitro and in vivo preclinical findings into clinical practice. In addition, the impact of DMF and MMF is often not clearly distinguishable and sometimes overlaps, making the true molecular mediators of therapeutic and side effects unclear. Thus, the interpretation of some results obtained in studies is inconsistent because of interchanging of in vitro and in vivo observed features of fumarate esters: while DMF demonstrates rapid and strong effects in cell culture studies, including nuclear factor erythroid 2-related factor 2 (NRF2) function activation and glutathione depletion, these observations may not exactly reflect systemic pharmacology and physiology dominated by MMF. Moreover, methanol, the co-product of DMF metabolism, may contribute to the observed DMF effects through increased production of reactive oxygen species, which could result in activation of NRF2-dependent mechanisms. This review highlights specific unresolved issues in DMF metabolism, which are sometimes overlooked.