In vivo effects of N-acetylcysteine on glutathione metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds

Abstract

N-acetylcysteine (NAC) was administered to rats in various combinations with an enzyme inducer (Aroclor 1254) and with depletors of reduced glutathione (GSH), i.e., diethyl maleate (DEM) and buthionine sulfoximine (BSO). NAC increased intracellular glutathione levels in erythrocytes and in liver and lung cells, and replenished its stores following depletion. It did not affect the concentrations nor the spectral properties of cytochromes P-450 in hepatic and pulmonary microsomes, whereas it stimulated, especially in Aroclor-pre-treated animals, cytosolic enzyme activities involved in NADP reduction (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase), in glutathione reduction (GSSG-reductase) and in the reductive detoxication of xenobiotics by-passing formation of reactive oxygen species (DT-diaphorase). In vivo treatment with the drug enhanced detoxication by liver and lung S-12 fractions of direct-acting mutagens (ICR 191, epichlorohydrin, 4-nitroquinolino-N-oxide and dichromate) and counteracted opposite effects triggered by administration of GSH depletors. The metabolic activation of procarcinogens (aflatoxin B1, 2-aminofluorene, cyclophosphamide, benzo[a]pyrene, a tryptophan pyrolysate product and cigarette smoke condensate) was inhibited by NAC in uninduced rats, while it was further stimulated in Aroclor-pre-treated animals. Additional assays, performed also with other enzyme inducers (phenobarbital and 3-methylcholanthrene) suggested that the effect of NAC on the metabolic activation of procarcinogens depends on the balance between an increased production of mutagenic metabolites (prevailing in induced animals) and their binding by intracellular thiols (prevailing under normal conditions). Thus, due to its dual role as a nucleophile and as a SH donor, NAC appears to exert protective effects by modulating glutathione metabolism and the biotransformation of mutagenic/carcinogenic compounds. This may have clinical relevance, since NAC is administered to individuals, such as cigarette smokers, who are more heavily exposed to GSH depletors and to carcinogenic agents.

Impact of 30-Day Oral Dosing with N-acetyl-l-cysteine on Sprague-Dawley Rat Physiology

“…Although the hver may play a significant role in NAC metabolism, several studies including our own have shown that liver GSH levels are not significantly increased following NAC (De Flora et al, 1985;McLellan et al, 1995;Pratt and loaimides, 1985), or oral GSH (Aw, Wierzbicka, and Jones, 1991) administration. NAC is a proven effective countermeasure for liver toxicity as a result of acetaminophen overdose (Corcoran and Wong, 1986;Lauterburg, Corcoran, and Mitchell, 1983) and this has lead to the hypothesis that NAC is chemoprotective because it boosts GSH biosynthesis in the liver.…”

“…Certain forms of cancer, neurodegenerative, and cardiovascular diseases have been linked to GSH depletion (Pastore et al, 2003). NAC supplementation increases GSH levels in humans (De Rosa et al, 2000;Pendyala and Creaven, 1995) and animals (De Flora et al, 1985;Lailey, 1997;McLellan et al, 1995). NAC stimulates glutathione-S-transferase (GST) transcription (Xia et al, 1996), which may contribute to its anti-oxidant properties.…”

The EUROSCAN Study

“…NAC is a precursor of extracellular and intracellular glutathione (GSH) (de Flora et al, 1985;Cotgreave et al, 1986) and it is widely used in the treatment of patients with chronic bronchitis and emphysema. It has become popular for its potent anti-oxidant/de-toxificant properties.…”

Pseudoporphyria Associated with Chronic Renal Failure: The Outcome from Oral N-Acetylcysteine Treatment in Three Cases

“…20 It can prevent increased oxidative stress following administration of radiocontrast agents and therefore has become widely used to prevent contrast-induced nephropathy. Meanwhile, Nacetylcysteine supplementation has been shown to be a promising therapy for oxidative stres and related complications including cardiovascular events in hemodialysis patients.…”