Studies on the mechanism of haloacetonitriles toxicity: Inhibition of rat hepatic glutathione S-transferases in vitro (original) (raw)

1989, Toxicology and Applied Pharmacology

Toxicol. Appl. Pharmacol. 100, 271-279. Acetonitrile (AN) and seven of its halogenated derivatives known to be water disinfectant by-products were evaluated for their action on hepatic cytosolic glutathione Stransferase (GST) activity using I-chloro-2.4-dinitrobenzene (CDNB) as substrate. Increasing concentrations of acetonitrile, monofluoroacetonitrile (MFAN), monochloroacetonitrile (MCAN), and monobromoacetonitrile (MBAN) up to 10 IIIM failed to produce 50% inhibition of the activity of GST enzyme. However, dichloroacetonitrile @CAN), trichloroacetonitrile (TCAN), dibromoacetonitrile (DBAN), and monoiodoacetonitrile (MIAN) were potent inhibitors with 150 values of 2.49, 0.34.0.82, and 4.44 mM. respectively. At concentrations equivalent to their 150, MIAN. DCAN, and DBAN decrease both apparent K,,, and V,,, of the enzyme activity toward glutathione (GSH) to 20-50% of control. TCAN significantly increases both apparent K, and I',,,,, for GSH to 650 and 120% of control values, respectively. The inhibitory effect of haloacetonitriles (HAN) on hepatic GST activity toward CDNB was found to be of a mixed type. The inhibitory effect of DCAN, DBAN. and TCAN on the hepatic GST activity was found to be reversible and the activity was completely recovered after dialysis of the inhibited enzyme. MIAN, however, inhibited GST activity in an irreversible manner. Haloacetonitriles induced inhibition of hepatic GST activity in vitro is consistent with that observed in vivo. The data presented in this study show that haloacetonitriles induced reversible inhibition of hepatic GST activities. and this effect may lead to decreased detoxification of other electrophilicchemicals.