Can N-acetyl-L-cysteine affect zinc metabolism when used as a paracetamol antidote?
N-Acetyl-L-cysteine (NAC) has long been used in the treatment of chronic lung diseases. Inhalation and oral administration of the drug are both effective in reducing mucus viscosity. In addition, NAC oral therapy allows to restore normal mucoprotein secretion in the long term. Although displaying heavy metal-complexing potential, NAC exerts no detectable influence on the metabolism of essential trace metals when used in the above context (i.e. at doses near 600 mg day-1). However, this may no longer be the case when NAC is used as an oxygen radical scavenger, like in the treatment of paracetamol poisoning. In the latter case, intravenous doses as high as 20 g day-1 are administered, which may induce excessive zinc urinary excretion. In order to allow a better appreciation of the risk of zinc depletion during NAC therapy, the present work addresses the role of this drug towards zinc metabolism at the molecular level. First, formation constants for zinc-NAC complexes have been determined under physiological conditions. Then, computer simulations for blood plasma and gastrointestinal fluid have been run to assess the influence of NAC and its metabolites (e.g. cysteine and glutathione) on zinc excretion and absorption. Blood plasma simulations reveal that NAC can effectively mobilise an important fraction of zinc into urinary excretable complexes as from concentrations of 10(-3) mol dm-3 (which corresponds to a dose of about 800 mg). This effect can still be enhanced by the action of NAC metabolites, among which cysteine is the most powerful zinc sequestering agent. In contrast, simulations relative to gastrointestinal conditions suggest that NAC should tend to increase zinc absorption, regardless of its dose.
Brumas
V
V
INSERM U305, Equipe Bioréactifs, Spéciation et Biodisponibilité, Université Paul Sabatier, Toulouse, France.
Hacht
B
B
Filella
M
M
Berthon
G
G
D000082:Acetaminophen / Q000506:poisoning*; D000111:Acetylcysteine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000931:Antidotes / Q000494:pharmacology*; D003198:Computer Simulation; D004068:Digestive System Physiological Phenomena; D006863:Hydrogen-Ion Concentration; D011199:Potentiometry; D015032:Zinc / Q000378:metabolism*
D000931:Antidotes; D000082:Acetaminophen; D015032:Zinc; D000111:Acetylcysteine