Metrifonate

Metrifonate (Trichlorfon) is an orally active, blood-brain barrier permeable organophosphorus compound that acts as a cholinesterase (ChE) inhibitor and regulates steroid synthesis-related proteins and functional enzymes. Metrifonate inhibits steroidogenic acute regulatory protein and P450 side-chain cleavage enzyme, and suppresses progesterone synthesis via the cAMP/PKA pathway. Metrifonate increases the levels of acetylcholine, norepinephrine and dopamine in the central nervous system as well as cerebral glucose utilization; enhances memory, learning and cognitive functions; induces cholinergic symptoms; and impairs reproductive functions. As a prodrug, Metrifonate is converted to Dichlorvos (HY-B1312), which inhibits cholinesterase, increases acetylcholine content in the brain and exhibits insecticidal activity. Metrifonate can be used in research related to Alzheimer's disease and endocrine disruption^[1][2][3]. In Vitro:Metrifonate (acting via its metabolite DDVP) is more active against butyrylcholinesterase than against human brain acetylcholinesterase^[1].
Metrifonate (0.04-25 μmol/l; 24 h) shows no cytotoxicity to MLTC-1 cells^[2].
Metrifonate (0.04-25 μmol/l; 24 h) dose-dependently inhibits progesterone synthesis stimulated by hCG, cholera toxin (CT) and forskolin in MLTC-1 cells in a dose-dependent manner. It downregulates the mRNA and protein expression of StAR, as well as the mRNA and protein expression of P450scc in hCG-stimulated MLTC-1 cells. Metrifonate also suppresses the activity of P450scc in MLTC-1 cells^[2]. In Vivo:Metrifonate (2.5-100 mg/kg; single dose, daily, p.o., b.i.d.; 21 days) enhances memory and cognitive function in normal, aged, and cholinergic deficit-induced rats, with dose-dependent increases in cortical acetylcholine, noradrenaline, and dopamine, and reversal of Scopolamine (HY-N0296)-induced EEG changes^[1].
Metrifonate (3-100 mg/kg; p.o.; single dose) induces dose-dependent, fully reversible cholinesterase inhibition in the brain, erythrocytes, and plasma of 3-month-old male Wistar rats, with ED₅₀ values of 90 mg/kg (brain) and 80 mg/kg (erythrocytes, plasma)^[3].
Metrifonate (3-100 mg/kg; p.o.; single dose) shows that food deprivation for 18 hours increases the sensitivity of 3-month-old male Wistar rats to metrifonate-induced cholinesterase inhibition, with ED₅₀ values of 60 mg/kg (brain) and 45 mg/kg (erythrocytes, plasma)^[3].
Metrifonate (3-100 mg/kg; p.o.; single dose) shows that 19-month-old male Wistar rats have increased sensitivity to metrifonate-induced cholinesterase inhibition compared to younger rats, with ED₅₀ values of 60 mg/kg (brain), 45 mg/kg (erythrocytes), and 20 mg/kg (plasma)^[3].