The effects of inhalation exposure to bromo-dichloromethane on specific rat CYP isoenzymes

Several cytochrome P450 (CYP) isoenzymes may be involved in the metabolism of bromo-dichloromethane (BDCM). a drinking water disinfection byproduct. A fter 4-h inhalation exposures of male F344 rats to BDCM between 100 and 320 0 p.p.m., hepatic microsomal methoxyresorufin demethylase (MROD), ethoxyres orufin de-ethylease (EROD) and pentoxyresorufin dealkylase (PROD) activitie s showed modest increases at low exposure levels and larger decreases at hi gh exposure levels, compared with controls. Western blots for CYP1A2 and CY P2B1 showed similar trends. In addition, p-nitrophenol hydroxylase (PNP) ac tivity was measured and Western blots for CYP2E1 were performed. CYP2E1 and CYP2B1 isoenzymes are known to metabolize BDCM (Thornton-Manning, J.R., Ga o, P., Lilly, P.D., Pegram, R.A., 1993. Acute bromodichloromethane toxicity in rats pretreated with cytochrome P450 inducers and inhibitors. The Toxic ologist 13: 361). When compared with a multiple gavage study of BDCM in fem ale F344 rats (Thornton-Manning, J.R., et al., 1994. Toxicology 94, 3-18), the results of the two studies for EROD, PROD, and PNP activities were qual itatively the same; PNP activity did not change, while both PROD and EROD a ctivities decreased at high exposures. In the current work. Western blots f or CYP2E1, CYP2B1 and CYP1A2 supported the results fr om the PNP, PROD and MROD activities, respectively. The decreases in MROD and PROD activities an d in Western blots for CYP1A2 and CYP2B1 at high exposures suggest that BDC M may be a suicide substrate for these CYP isoenzymes. Other important conc lusions that can be drawn from the comparison between the current and prior work are that the liver response is similar for both sexes, and it is also similar for inhalation and gavage exposures under these conditions. Finall y, the decrease in EROD activity at high doses. found in both studies, may be a further reflection of CYP1A2 activity, since little or no CYP1A1 activ ity is normally found in uninduced rat liver and CYP1A2 is known to metabol ize ethoxyresorufin. although much more slowly than CYP1A1. (C) 2001 Elsevi er Science Ireland Ltd. All rights reserved.