Glutathione///ALA

[Guest guest]

Very interesting paper from Moria's excellent site. Those

interested in glutathione... wonder if you would share your

thoughts after reading this paper. It shows how ALA and

glutathione work together.

Interesting that Ala and glutathione cannot chelate out

methylmercury.

~^^V^^~

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi

Toxicol Appl Pharmacol 1992 May;114(1):88-96

Effect of lipoic acid on biliary excretion of glutathione

and metals.

Gregus Z, Stein AF, Varga F, Klaassen CD

Department of Pharmacology, University Medical School of Pecs,

Hungary.

Several metals are excreted in bile as glutathione

complexes, and

their

biliary excretion is facilitated by increased hepatobiliary

transport

of

glutathione. The present study analyzed the effect of

lipoic acid

(LA;

thioctic acid; 37.5-300 mumol/kg, iv), an endogenous

disulfide which

can be

reduced in vivo to a dithiol, on the hepatobiliary

disposition of

glutathione-related thiols and the biliary excretion of

metals (10

mumol/kg,

iv) in rats. Administration of LA enhanced the biliary

excretion of

reduced

glutathione in a dose-dependent fashion. Despite increasing

glutathione

output, LA (150 mumol/kg, iv) did not increase, but rather

decreased,

the

biliary excretion of methylmercury, cadmium, zinc, and

copper, which

are

transported into bile in a glutathione-dependent manner, as

indicated

by a

marked reduction in their biliary excretion after diethyl

maleate-induced

glutathione depletion. In contrast, biliary excretion of

inorganic

mercury,

which is minimally affected by glutathione depletion, was

dramatically

enhanced (12- to 37-fold) by LA administration. Following

injection

of LA,

the concentrations of endogenous disulfides in arterial

blood plasma

(e.g.,

cystine, glutathione disulfide, cysteine-glutathione,

protein-cysteine, and

protein-glutathione mixed disulfides) were considerably

diminished,

while the

levels of endogenous thiols (e.g., glutathione and

cysteine) were

increased.

This finding indicates that LA, probably after enzymatic

conversion

to

dihydrolipoic acid, can reduce endogenous disulfides to

thiols. It

appears

that LA induces the transport of glutathione into bile by the

temporary

formation of dihydrolipoic acid-glutathione mixed

disulfide, which

after

being translocated into bile is cleaved to LA and reduced

glutathione.

Because the glutathione molecule thus transported into bile

cannot

complex

metals at the thiol group, this might be the mechanism for the

observed

failure of the LA-induced increase in biliary excretion of

glutathione to

enhance the hepatobiliary transport of metals that are

transported

into bile

as glutathione complexes (i.e., methylmercury, cadmium,

zinc, and

copper).

The observations also raise the possibility that endogenous

dihydrolipoic

acid, by forming a stable complex with mercuric ion, may

play the

role of a

carrier molecule in the hepatobiliary transport of

inorganic mercury.

This is an excellent and useful paper. I suggest people get

the

actual paper

and read it rather than relying on the abstract if they are

going to

draw

conclusions about what they will or won't do.

This paper actually did have a large influence on

determining the LA

chelation protcol as follows: I don't suggest LA until some

months

after

organic mercury exposure ceases so that it all converts to

inorganic

form, I

suggest using half maximum zinc dosage once chelation

starts, and I

suggest

not chelating more than half the time and taking frequent

breaks from

it to

avoid perturbing copper and zinc balance.

Unusually for a biomedical paper these guys presented their

data in

enough

detail that I was able to extract a rate law for LA and

mercury - and

found

it was the same as the info I got on rates from the Russian

paper on

LA for

mercury poisoning.

This is a rat paper, not one with human subjects, but most

of the

fundamentals of biochemistry remain the same among all

mammals. The

things

you have to watch out for are papers where vitamin C is

relevant

(since rats

make their own and we need to eat it) and papers where the

blood/brain

barrier is relevant (since ours works much differently and

much

better than

the one rats have).

Andy Cutler