Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers.
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.
Van Schooten
Frederik Jan
FJ
Department of Health Risk Analysis and Toxicology, Maastricht University, The Netherlands.
Besaratinia
Ahmad
A
Besarati Nia
Ahmad
A
De Flora
Silvio
S
D'Agostini
Francesco
F
Izzotti
Alberto
A
Camoirano
Anna
A
Balm
Alfons J M
AJ
Dallinga
Jan Willem
JW
Bast
Aalt
A
Haenen
Guido R M M
GR
Van't Veer
Laura
L
Baas
Paul
P
Sakai
Harumasa
H
Van Zandwijk
Nico
N
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*
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D015415:Biomarkers; D018736:DNA Adducts; D016166:Free Radical Scavengers; D003367:Cotinine; D000111:Acetylcysteine