Chemopreventive activity of thiol conjugates of isothiocyanates for lung tumorigenesis.
A series of L-cysteine (L-Cys), glutathione (GSH), and N-acetyl-L-cysteine (NAC) conjugates of phenethyl (PEITC), benzyl (BITC), and 6-phenylhexyl isothiocyanate (PHITC) were studied for their inhibitory activity toward metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mouse lung microsomes. Selected compounds, PEITC, PEITC-GSH, PEITC-NAC and PHITC-NAC, were also assayed for the potential chemopreventive activity toward NNK-induced lung tumorigenesis in A/J mice. Results showed that PEITC and its conjugates inhibited NNK metabolism with decreasing potency: PEITC < PEITC-GSH > PEITC-Cys > PEITC-NAC. PHITC and its GSH and NAC conjugates exhibited nearly 10 times higher inhibitory activity toward NNK metabolism than the PEITC counterparts. In the tumor bioassay, as expected, the conjugates exhibited inhibitory activity against lung tumorigenesis induced by NNK. PEITC-GSH was not inhibitory at 4 micromol/mouse, but it inhibited approximately 32% of lung tumor multiplicity at 8 micromol/mouse. PEITC-NAC at 5 and 20 micromol/mouse both inhibited approximately 30% tumor multiplicity. Among all the conjugates examined, PHITC-NAC was the most potent. At a 5-micromol dose, it completely inhibited tumor multiplicity and incidence to the background level observed in the control group. These results revealed that the structure-activity relationships of the conjugates are similar to those found with their parent isothiocyanates (ITCs), i.e., the potency increased with the increasing alkyl chain length from two to six carbons in arylalkyl ITCs, suggesting that a common active species is involved. The inhibitory activity of ITC conjugates and the expected low toxicity make thiol conjugates of ITC a promising new series of chemopreventive agents.
Jiao
D
D
Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, NY 10595, USA.
Smith
T J
TJ
Yang
C S
CS
Pittman
B
B
Desai
D
D
Amin
S
S
Chung
F L
FL
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D005260:Female; D017879:Isothiocyanates / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D009602:Nitrosamines; D013438:Sulfhydryl Compounds; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone