Work

N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) as a novel chelator for Wilson's disease

Year: 2025

Type: article

Abstract: Wilson’s Disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene. These mutations lead to defective copper (Cu) transport and to accumulation of Cu in tissues, primarily in the liver and brain. Current treatment options such as D-penicillamine, trientine, and zinc salts focus on increasing Cu excretion or reducing Cu absorption, but often cause debilitating side effects. N,N’ bis-(2-mercaptoethyl)isophthalamide (NBMI) is a lipophilic thiol-based compound originally developed for environmental decontamination. It has been shown to chelate toxic metals such as mercury, lead, and cadmium. This study was designed to evaluate the efficacy of NBMI to mitigate Cu overload using both in vitro and in vivo models of WD. HepG2 cells with the ATP7B gene knocked down had increased sensitivity to copper sulfate (CuSO 4 ) compared to wild-type (WT) cells, validating the cell model for WD. Pretreatment with NBMI (2.5-50 μM) improved cell viability, reduced Cu-induced oxidative stress, decreased metallothionein levels, mitigated resulting DNA damage, and reduced overall levels of free intracellular Cu. In an established toxic milk mouse (tx-J) model of WD, 1% dietary NBMI effectively lowered hepatic, cerebral, and renal Cu levels. Treatment with 1% NBMI also improved liver function, as evidenced by reduced ALT levels and normalized hepatocyte morphology. Tx-J mice displayed higher liver-to-body weight ratios compared to WT mice, and treatment with 1% NBMI effectively reduced this ratio. While NBMI did not impact the elevated white blood cell counts and low platelet levels characteristic of tx-J mice, it also did not cause any detrimental effects on red blood cell, hemoglobin, and hematocrit levels. High dose NBMI also restored homeostasis of other dysregulated essential metal ions in tx-J mice. These findings suggest that dietary administration of NBMI effectively chelates excess free Cu, ameliorates WD symptoms and offers a promising alternative to existing chelators. • ATP7B KD HepG2 cells exhibited heightened sensitivity to CuSO 4 -induced cell death. • NBMI protected against Cu-induced cell death and improved Cu and Fe homeostasis. • NBMI diet reduced hepatic Cu levels, liver weights and ALT levels in tx-J mice. • NBMI diet lowered brain Cu and corrected brain Fe and Zn deficiency in tx-J mice.

Source: Free Radical Biology and Medicine

DOI: 10.1016/j.freeradbiomed.2025.02.046

Authors: Rajitha Gadde, Shrey Shah, Mark Böhlke, Jonghan Kim, Swati Betharia

Institutions: Massachusetts College of Pharmacy and Health Sciences, University of Massachusetts Lowell

Language: English

Topic: Trace Elements in Health

Subfield: Nutrition and Dietetics

Field: Nursing

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,240