Effect of hexachlorophene, tribromsalan, trichlorcarban and cloflucarban on hexobarbital sleeping time and hepatic drug-metabolizing enzyme activity in vitro in the rat

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Abstract

Oral administration of the antibactenals hexachlorophene, tribromsalan and trichlorcarban at doses of 50, 10 and 40 mg/kg, respectively, caused significant increases in hexobarbital sleeping time in male Wistar rats, while an oral dose of 40 mg/kg of cloflucarban gave only a slight increase. The four halogenated antibacterials inhibited hepatic microsomal aminopyrine N-demethylase and aniline hydroxylase activities in vitro but had no effect on hepatic microsomal NADPH-cytochrome c reductase activity. The addition of each of the antibacterials to hepatic microsomes produced a type I difference spectrum. The spectral binding constants for interaction of hexachlorophene, tribromsalan, trichlorcarban and cloflucarban with hepatic microsomal cytochrome P450 were 33, 62, 66 and 40 μM respectively. The per cent of in vitro inhibition of hepatic microsomal mixed-function oxidase activity by these agents increased with increasing incubation times. The addition of bovine serum albumin to the incubation mixtures partially reversed the inhibition of microsomal drug metabolism caused by the halogenated antibacterial agents in vitro.

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    This work was supported by grants from the Food and Drug Administration (FD-00041) and from the National Institutes of Health (ES-00210). This manuscript was issued as Technical Paper 4644 from the Oregon Agricultural Experiment Station.

    United States Environmental Protection Agency, Toxic Substance Control Office, Air and Hazardous Materials Division, Chicago, II 60604.

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