Carcinogenesis, Vol 18, 2143-2147, Copyright © 1997 by Oxford University Press
D Jiao, TJ Smith, CS Yang, B Pittman, D Desai, S Amin and FL Chung
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.
ARTICLES
Chemopreventive activity of thiol conjugates of isothiocyanates for lung tumorigenesis
Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, NY 10595, USA.
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