Effect of ozone on drug-induced sleeping time in mice pretreated with mixed-function oxidase inducers and inhibitors

Abstract

Prior studies have shown that ozone (O 3) increases pentobarbital (PEN)-induced sleeping time (S.T.) in female mice, rats, and hamsters. To investigate some potential mechanisms producing these effects, we measured zoxazolamine-induced paralysis time and thiopental- and hexobarbital-induced S.T., all of which were prolonged significantly in mice following a 5-hr exposure to 1960 μg O 3/m 3 (1 ppm). To probe the effect of O 3 exposure on the drug metabolism microsomal monooxygenase system, CD-1 mice were pretreated with mixed-function oxidase inducers [PEN, phenobarbital, pregnenolone-16α-carbonitrile, and β-naphthoflavone (BNF)] or inhibitors (SKF 525A and piperonyl butoxide) prior to a 5-hr exposure to 1960 μg O 3/m 3 (1 ppm). In CD-1 mice, pretreatment with PEN caused no effects on PEN-induced S.T. For all other compounds, the PEN-induced S.T. of CD-1 mice was significantly decreased, irrespective of whether the animals were exposed to air or O 3. Ozone exposure significantly increased PEN-induced S.T. equivalently in the vehicle- and inducer-pretreated animals. Similar studies were conducted in DBA and C57BL mice pretreated with BNF. DBA mice responded similarly to CD-1 mice. However, with C57BL mice, O 3 significantly increased PEN-induced S.T. in the vehicle, but not in the BNF group. When CD-1 mice were pretreated with inhibitors, a generally increased magnitude of the O 3 effect was observed with increasing doses of inhibitor. These data suggest that O 3 exposure may affect several aspects of drug metabolism and distribution.