Induction of rat hepatic drug metabolizing enzymes by dimethylcyclosiloxanes

Low molecular weight dimethylcyclosiloxanes (DMCS) are important precursors in the synthesis of polydimethysiloxane polymers widely used in industry, and in medical and personal care products. The objective of this study was to characterize the ability of two DMCS, octamethylcyclosiloxane (D4) and d ecamethylcyclopentasiloxane (D5) to induce drug metabolizing enzymes in rat s. Male and female Sprague-Dawley rats were administered 1, 5, 20, or 100 m g/kg D4 or D5 in corn oil daily by gavage for 4 days. Changes in the levels of activity and/or immunoreactivity of CYP1A1/2, CYP2B1/2, CYP3A1/2 and NA DPH cytochrome P-450 reductase in liver microsomes were examined. Significa nt increases were observed in the liver to body weight ratio in female rats administered either D4 or D5 at doses greater than or equal to 20 mg/kg. I ncreases in the liver to body weight ratio were observed in male rats treat ed with greater than or equal to 100 mg/kg D5 but not with D4. Relatively l arge increases in CYP2B1/2 enzymatic activity and immunoreactive protein we re observed with increasing concentrations of both D4 and D5. Significant i ncreases in 7-pentoxyresorufin O-depentylase (PROD) activity were also dete cted in male and female rats given D4 at doses greater than or equal to 5 m g/kg. D5 increased PROD activity in male rats at doses greater than or equa l to 20 mg/kg and in female rats at doses greater than or equal to 5 mg/kg. 7-Ethoxyresorufin O-deethylase (EROD) activity was increased in both male and female rats receiving greater than or equal to 20 mg/kg D4 or greater t han or equal to 5 mg/kg D5; however, no changes were detected in CYP1A1/2 i mmunoreactive protein in rats of either sex. D4 and D5 caused significant i ncreases in CYP3A1/2 immunoreactive protein in only male rats treated with 100 mg/kg of either compound. However, significant increases were detected in CYP3A1/2 immunoreactive protein in female rats at D4 doses greater than or equal to 20 mg/kg and D5 doses greater than or equal to 5 mg/kg. Inducti on of NADPH cytochrome P-450 reductase immunoreactive protein was observed with D4 in female rats and in both male and female rats with D5. Induction of CYP2B/1/2, CYP3A1/2 and NADPH cytochrome P-450 reductase was observed in rats treated with 50 mg/kg phenobarbital by intraperitoneal injection. Max imal CYP2B induction detected with D4 was approximately 50% of the increase observed with phenobarbital. In summary, D4 and D5 induced CYP2B1/2 in adu lt rat liver in a manner similar to that observed with phenobarbital; howev er, differences were observed between D4 and D5 in their ability to induce CYP3A1/2 and NADPH cytochrome P-450 reductase. Female rats were more sensit ive to the inductive properties of low doses of both DMCS than male rats wh ereas male rats were more responsive to phenobarbital induction. (C) 2000 E lsevier Science Ireland Ltd. All rights reserved.