From my scribbled notes on the research, mostly in animals:

There is no alternative pathway for DCA clearance other than the MAAI (also known as GSTZ1-1) mediated transformation.

Prolonged continued use of dca will deplete MAAI

MAAI pathway is also used to breakdown tyrosine catabolites. If MAAI is depleted/inhibited, toxic concentrations of tryosine intermediates such as maleylacetone and succinylacetone accumulate.

Patients with acquired deficiency of MAAI via dca are at increased risk of drug & chemical induced toxicity

DCA indiced inactivation of MAAI leads to formation of MAA derived intermediate, maleylaceton which is a biomarker for dca associated toxicities

Urinary excretion of unchanged dca increased with age. Oxalate (the end product of DCA metabolism) decreases. Plasma and urinary levels of maleylacetone (natural substrate for MAAI enzyme increases with age. Liver MAAI activity inhibited equally by DCA in all age groups.

In animals it took 8 weeks for MAAI to return to control levels after chronic administering of dca.

Hypothetically, chronic dca could mimic the symptoms of Tyrosinemia type 1. The catabolite succinylacetone is an irreversible inhibitor of aminolevulinic acid dehydratase ALAD. This depletes Heme - required by enzymes synthesizing vascular modulators leading to decreased renal NOS activity and increased kidney microsomal heme oxygenase activity by 27%. (But in animals this did not increase blood pressure)

Delta aminolevulinic acid (delta ALA) implicated in neurological complications of porphyria & tyrosinemia type 1 & elevated in urine of dca treated animals - delta ALA reduced myelin lipids and proteins

Melatonin protects against oxidative stress caused by delata ALA.

DCA itself directly induces reversible inhibition of myelin related proteins

*** This could be interesting - heriditary tyrosinemia type 1 leads to chronic stress which activates Akt survival signal - inhibits apoptosis in liver - inhibits mitochondrial mediated apoptosis through BAD & Bcl-X(l) & Bcl-2

In a nutshell, chronic prolonged use of dca can dominate and exhaust a chemical pathway used to breakdown phenylalanine and tyrosine, accumulating poisonous catabolites in the body. If this mimics heriditary tyrosinemia type 1 it might lead to the shutdown of the mitochondrial mediated apoptopic pathway.

Again I stress this is a hypothesis only. We would need to somehow check the dca resistant people for increased maleylacetone and succinylacetone and come up with a fix for it - somehow increasing MAAI, or a drug that breaksdown the tyrosine catabolites. Alternatively we need a dosing and time regimen for dca that ensures MAAI does not get depleted. I welcome all comments and opinions.

Regards to you all

Mack