Humantenine

Humantenine is a highly toxic indole alkaloid from Gelsemium elegans (Gardn. & Champ.) Benth. that binds to RNA m6A modification regulatory proteins (ALKBH5, METTL). Humantenine stably binds via hydrogen bonding and hydrophobic interactions and disrupts the m6A methylation level of target genes, thereby impairing the expression of intestinal epithelial cell tight junction and cytoskeleton-related genes, causing intestinal barrier dysfunction and significant intestinal cytotoxicity. The intraperitoneal injection LD₅₀ values of Humantenine are <1 mg/kg in mice, 1.2 mg/kg in male rats and 1.5 mg/kg in female rats, respectively. Species differences exist in the metabolism of Humantenine in human, porcine, goat and rat liver microsomes, and demethylation, dehydrogenation and oxidation occur in liver microsomes^{[1][2][3][4][5]}. In Vitro:Humantenine (400 μM; 48 h) induces concurrent alterations in m6A modification and expression of mRNA for 1401 genes in the human colon cancer cell line HCT116, leading to the enrichment of KEGG and GO annotation terms related to actin cytoskeleton, tight junctions and adherens junctions, differential expression of 11 RNA m6A methylation regulators, and dysregulated m6A methylation levels of target genes^[1].
Humantenine (10 mM; 1 h) undergoes metabolism via 5 pathways in human liver microsomes, with demethylation as the major metabolic pathway, producing 9 distinct metabolites with specific semi-quantitative peak intensities^[2]. In Vivo:Humantenine (0.1 mg/kg; i.v.; single dose) reaches a maximum plasma concentration of 11.5 ng/mL in male Sprague-Dawley rats, with an elimination half-life of 1.5 h^[3].
Humantenine (0.1 g/kg, dose converted from total Gelsemium elegans powder; administered via oral gavage; single dose) reaches the peak time at 0.083 h in female SD rats, with an elimination half-life as long as 29.03 h, exhibiting pharmacokinetic characteristics of rapid absorption and slow elimination ^[4].