title: Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers.
abstract: N-Acetyl-L-cysteine (NAC) has been shown to exert cancer-protective mechanisms and effects in experimental models. We report here the results of a randomized, double-blind, placebo-controlled, Phase II chemoprevention trial with NAC in healthy smoking volunteers. The subjects were supplemented daily with 2 x 600 mg of oral tablets of NAC (n = 20) or placebo (n = 21) for a period of 6 months, and internal dose markers [plasma and bronchoalveolar lavage (BAL) fluid cotinine, urine mutagenicity], biologically effective dose markers [smoking-related DNA adducts and hemoglobin (Hb) adducts], and biological response markers (micronuclei frequency and antioxidants scavenging capacity) were assessed at both pre- and postsupplementation times (T(0) and T(1), respectively). Overall, the internal dose markers remained unchanged at T(1) as compared with T(0) in both NAC and placebo groups. When quantifying the biologically effective dose markers, we observed an inhibitory effect of NAC toward the formation of lipophilic-DNA adducts (5.18 +/- 0.73 versus 4.08 +/- 1.03/10(8) nucleotides; mean +/- SE; P = 0.05) as well as of 7,8-dihydro-8-oxo-2'-deoxyguanosine adducts in BAL cells (3.9 +/- 0.6 versus 2.3 +/- 0.2/10(5) nucleotides; P = 0.003). There was no effect of NAC on the formation of lipophilic-DNA adducts in peripheral blood lymphocytes or polycyclic aromatic hydrocarbon-DNA adducts in mouth floor/buccal mucosa cells or 4-aminobiphenyl-Hb adducts. Likewise, quantification of the biological response markers showed an inhibitory effect of NAC on the frequency of micronuclei in mouth floor and in soft palate cells (1.3 +/- 0.2 versus 0.9 +/- 0.2; P = 0.001) and a stimulating effect of NAC on plasma antioxidant scavenging capacity (393 +/- 14 versus 473 +/- 19 microM Trolox; P = 0.1) but not on BAL fluid antioxidant scavenging capacity. We conclude that NAC has the potential to impact upon tobacco smoke carcinogenicity in humans because it can modulate certain cancer-associated biomarkers in specific organs.
authors.affiliation: Department of Health Risk Analysis and Toxicology, Maastricht University, The Netherlands.
authors.forename: Frederik Jan
authors.initials: FJ
authors.lastname: Van Schooten
authors.forename: Ahmad
authors.initials: A
authors.lastname: Besaratinia
authors.forename: Ahmad
authors.initials: A
authors.lastname: Besarati Nia
authors.forename: Silvio
authors.initials: S
authors.lastname: De Flora
authors.forename: Francesco
authors.initials: F
authors.lastname: D'Agostini
authors.forename: Alberto
authors.initials: A
authors.lastname: Izzotti
authors.forename: Anna
authors.initials: A
authors.lastname: Camoirano
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: Balm
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Dallinga
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
authors.forename: Guido R M M
authors.initials: GR
authors.lastname: Haenen
authors.forename: Laura
authors.initials: L
authors.lastname: Van't Veer
authors.forename: Paul
authors.initials: P
authors.lastname: Baas
authors.forename: Harumasa
authors.initials: H
authors.lastname: Sakai
authors.forename: Nico
authors.initials: N
authors.lastname: Van Zandwijk
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000627:therapeutic use*; D000284:Administration, Oral; D000328:Adult; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D003367:Cotinine / Q000378:metabolism; D018736:DNA Adducts; D004249:DNA Damage; D004311:Double-Blind Method; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009152:Mutagenicity Tests; D009369:Neoplasms / Q000209:etiology / Q000517:prevention & control*; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D000975:Antioxidants; D015415:Biomarkers; D018736:DNA Adducts; D016166:Free Radical Scavengers; D003367:Cotinine; D000111:Acetylcysteine