ISSN:
1432-0843
Keywords:
Key words: Thioredoxin – Thioredoxin reductase – Disulphides – Growth inhibition
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract. The thioredoxin/thioredoxin reductase system is important for several aspects of the regulation of cellular proliferation by both intracellular and extracellular mechanisms. The effects of n-butyl 2-imidazolyl disulfide (III-2), 1-methylpropyl 2-imidazolyl disulfide (IV-2), and n-decyl 2-imidazolyl disulfide (VII-2) on purified human placental thioredoxin reductase activity were examined. The analogues were competitive inhibitors with DTNB for reduction by thioredoxin reductase, with K i values for III-2, IV-2, and VII-2 being 3.3, 13.0, and 8.6 μM, respectively. The inhibition was noncompetitive with reduced nicotinamide adenine dinucleotide phosphate (NADPH). None of the analogues was a suicide substrate inhibitor of the flavoenzyme. III-2 and VII-2 were metabolized by thioredoxin reductase at about half the rate of DTNB, whereas IV-2 was not detectably metabolized. The second order rate constants for the reactions of III-2 and IV-2 with reduced GSH were 931 and 91 M – 1 s – 1, respectively. The lower reactivity of IV-2 with reduced GSH and the lack of the analogue’s metabolism by thioredoxin reductase may be due to the more sterically hindered structure of this analogue. The 50% inhibitory concentrations (IC50 values) for the inhibition of serum-dependent cellular proliferation of Swiss 3T3 murine fibroblasts by III-2, IV-2, and VII-2 were 2.0, 3.5, and 4.0 μM, respectively. IV-2 was considerably more potent as an inhibitor of the thioredoxin-dependent cellular proliferation of Swiss 3T3 fibroblasts, showing an IC50 value of 60 nM. Thus, inhibition of cellular proliferation by alkyl 2-imidazolyl disulfide analogues may involve interaction with thioredoxin, thioredoxin reductase, or an alternative target that is redox-regulated by thioredoxin.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00685570
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