Description
Summary Abstract
Diisopropylamine Dichloroacetate (DADA; CAS 660-27-5; C8H17Cl2NO2) is the diisopropylamine salt of dichloroacetic acid, MW 230.13 g/mol. First isolated as the primary active constituent of “Vitamin B15” (pangamic acid) in the 1950s, it has been continuously prescribed in Japan as a hepatoprotective agent under the trade name Liverall. Upon aqueous dissociation, DADA releases diisopropylamine (DIPA) and dichloroacetate (DCA), which act synergistically on distinct cellular targets: DIPA donates methyl groups driving endogenous choline and lecithin synthesis, while DCA selectively inhibits pyruvate dehydrogenase kinase 4 (PDK4), reactivating the mitochondrial pyruvate dehydrogenase (PDH) complex and forcing metabolism from aerobic glycolysis to oxidative phosphorylation. A 2005 multicenter RCT (n = 127) demonstrated 87.8% symptomatic improvement in NAFLD at 120 mg/day, with ALT normalization in 55–69% of patients and an exemplary safety profile. Emerging oncology data show a breast-cancer IC50 of 7.1 mmol/L and a 50% complete tumor-regression rate in combination with fenbendazole, alongside potent radiosensitization of esophageal squamous cell carcinoma via ROS induction.
Clinical Indications
DADA’s dual mechanism supports investigation across metabolic and oncological contexts:
- Non-Alcoholic Fatty Liver Disease (NAFLD): Lipotropic clearance of intrahepatic fat via VLDL assembly, with documented ALT normalization in randomized controlled trials.
- Viral-Induced Multiorgan Failure: PDK4 inhibition restores ATP to critically depleted cardiac, hepatic, and skeletal-muscle compartments during hyperinflammatory viral events such as severe influenza.
- Oncological Radiosensitization / Tumor Metabolic Reprogramming: Forced reactivation of oxidative phosphorylation in glycolytic tumors generates lethal mitochondrial ROS, sensitizing esophageal, breast, and lung carcinoma to radiotherapy and combinatorial agents.
- Hepatic Fibrosis and Cholestasis: Selective inhibition of hepatic stellate cell proliferation and upregulation of Na⁺/K⁺-ATPase drive bile secretion and extracellular-matrix downregulation.
- Drug-Induced Hepatotoxicity Rescue: Adjunctive hepatoprotection during arsenic-trioxide chemotherapy, enabling continuous oncological dosing without liver-function interruption.
Contraindications
- Severe Renal Impairment: DCA is cleared by GSTZ1-mediated hepatic metabolism; impaired renal excretion of metabolites may increase systemic accumulation risk.
- Concurrent GSTZ1-Modifying Agents: Agents that further deplete GSTZ1 activity may unpredictably prolong DCA half-life and alter kinetics.
- G6PD Deficiency (if formulated with reducing excipients): Caution warranted given potential ROS dynamics at high concentrations.
- Pregnancy / Lactation: Absence of controlled human gestational safety data; fetal risk cannot be excluded.
Mechanism of Action (MOA)
DADA dissociates in aqueous physiological environments into two bioactive constituents that intercede across mitochondrial, lipid-anabolic, and membrane-structural pathways:
PDK4 Inhibition → Metabolic Switch
The dichloroacetate (DCA) moiety directly inhibits pyruvate dehydrogenase kinase 4 (PDK4), preventing phosphorylation of the pyruvate dehydrogenase (PDH) complex. Reactivated PDH catalyzes pyruvate → acetyl-CoA, restoring entry into the TCA cycle and mitochondrial ATP synthesis. In neoplastic cells relying on the Warburg effect, this forces dysfunctional mitochondria into electron-transport overload, generating lethal reactive oxygen species (ROS) and activating caspase-3/7 and PARP cleavage.
Lipotropic Choline Synthesis
The diisopropylamine (DIPA) moiety acts as a potent methyl donor, fueling endogenous methionine and choline synthesis. The resulting lecithin (phosphatidylcholine) complexes with intrahepatic triglycerides and cholesterol to form soluble VLDL particles, exporting pathogenic fat from the hepatic parenchyma. Simultaneously, HMG-CoA reductase activity and fatty-acid synthesis cascades are downregulated, reducing de novo lipid deposition.
Membrane Stabilization & Cholestasis Resolution
DADA drives sequential phospholipid methylation, enhancing hepatocyte membrane fluidity. This upregulates Na⁺/K⁺-ATPase pump activity—the primary osmotic driver of bile secretion—resolving intrahepatic cholestasis, clearing biliary sludge, and restoring bile-acid transport. Accelerated membrane repair also increases hepatocyte oxygen-utilization coefficients after ischemic or toxic injury.
Anti-Fibrotic & Keratinocyte Modulation
In fibrotic models, DADA selectively inhibits activated LX-2 hepatic stellate cell proliferation while sparing healthy hepatocytes, via downregulation of TGF-β1, α-SMA, desmin, and Type I collagen. In keratinocytes, the DCA moiety promotes simultaneous proliferation and terminal differentiation (Keratin K1 upregulation, cornified-envelope formation), suggesting dermatological wound-healing applications.
Key Features & Specifications
DADA combines structural duality with a demonstrated clinical-safety record:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| IUPAC Name | 2,2-dichloroacetic acid; N-propan-2-ylpropan-2-amine |
| CAS Number | 660-27-5 |
| Molecular Formula | C8H17Cl2NO2 |
| Molecular Weight | 230.13 g/mol |
| PubChem CID | 68606 (Diisopropylamine dichloroacetate) |
| Synonyms | Dipromonium, Liverall, Oxypangam, Disotat, Kalodil, Dapocel, Vasculopatina, Tensicor, Dedyl, Diedi, pangamic acid active constituent |
| Form / Variation | Amino Blend 20 mL (SKU A-004-F) / 250 MG Capsules (SKU C-010) / Liquid 300 MG/mL 30 mL (SKU L-019) |
Storage, Safety, and Handling
Storage Protocol
Lyophilized DADA is thermally sensitive; store desiccated at 2–8 °C, protected from light and moisture. The lyophilized form is manufactured with sodium gluconate (1.05:1 DADA:gluconate ratio, pH 4.8–5.8) to ensure structural integrity and extended shelf life. Reconstitute in 5% or 10% glucose solution or 0.9% sodium chloride immediately before use; do not subject reconstituted solution to elevated temperatures.
Handling & Compliance
Handle with standard laboratory PPE (gloves, eye protection) and sterile technique for injectable preparations. DADA exhibits mild mutagenicity signals in Ames-assay testing with S9 activation at microgram concentrations; chronic high-dose exposure should be monitored in a research context. Diisopropylamine is listed as a banned vasodilator by the FEI/International Federation of Horseracing Authorities; relevant regulatory bodies should be consulted when applicable.