Haloacetonitrile excretion as thiocyanate and inhibition of dimethylnitrosamine demethylase: A proposed metabolic scheme

Abstract

Haloacetonitriles, contaminants present in chlorinated drinking water, were administered orally to rats, and the urinary excretion of thiocyanate was measured as an index of cyanide release. The urinary excretion of thiocyanate accounted for 14.2% of the dose of monochloroacetonitrile; 7.7–12.8% of the dose of bromochloro‐, dichloro‐, and dibromoacetonitrile; and 2.25% of the dose of trichloroacetonitrile. The haloacetonitriles inhibited rat‐liver microsomal dimethylnitrosamine (DMN) demethylase in an in vitro assay system. Dibromo‐ and bromochloroacetonitrile were the most potent inhibitors of DMN demethylase, with K _i = 3–4 × 10 ⁻⁵ M; dichloro‐ and trichloroacetonitrile were the next most potent, with K¡ = 2 × 10 ⁻⁴ M; and monchloroacetonitrile was the least potent inhibitor, with K _i = 9 × 10 ⁻² M. Trichloroacetonitrile, but not dibromoacetonitrile, when administered orally inhibited hepatic DMN demethylase activity. The relative capacity of the haloacetonitriles to inhibit DMN demethylase and to be excreted as thiocyanate did not correlate.