Effects of pretreatment with CYP enzyme inducers on the epoxidation of (R)-VCH and (S)-VCH
| Metabolite | Treatment Group | Mouse | Rat | ||
|---|---|---|---|---|---|
| (R)-VCH | (S)-VCH | (R)-VCH | (S)-VCH | ||
| VCH-1,2-epoxide | Control | 75 ± 9 | 30 ± 4 | 38 ± 7 | 19 ± 7 |
| Acetone | 134 ± 11 (1.8) | 66 ± 8 (2.2) | 79 ± 7 (2.1) | 37 ± 0 (2.0) | |
| Phenobarbital | 462 ± 30 (6.2) | 182 ± 13 (6.1) | 83 ± 8 (2.2) | 36 ± 11 (1.9) | |
| VCH | 231 ± 16 (3.1) | 101 ± 16 (3.4) | 68 ± 8 (1.8) | 68 ± 8 (1.8) | |
| VCH-7,8-epoxide | Control | 30 ± 4 | 56 ± 7 | 30 ± 4 | 33 ± 7 |
| Acetone | 40 ± 6 | 56 ± 7 | 30 ± 4 | 37 ± 4 | |
| Phenobarbital | 58 ± 2 (1.9) | 90 ± 12 (1.6) | 30 ± 3 | 37 ± 6 | |
| VCH | 58 ± 8 (1.9) | 107 ± 11 (1.9) | 35 ± 12 | 38 ± 5 | |
| VCD | Control | N.D. | N.D. | N.D. | N.D. |
| Acetone | 7 ± 11-150 | 2 ± 1 | N.D. | N.D. | |
| Phenobarbital | 8 ± 21-150 | 3 ± 3 | N.D. | N.D. | |
| VCH | 8 ± 2 | 7 ± 2 | N.D. | N.D. | |
Formation of VCH-1,2-epoxide, VCH-7,8-epoxide, and VCD (nmol/mg of protein) from (R)-VCH or (S)-VCH after 60-min incubations with hepatic microsomes from B6C3F1 mice or Fischer 344 rats pretreated with acetone (1.0% in drinking water × 5 days), phenobarbital (80 mg/kg × 5 days, i.p.), or VCH (7.5 mmol/kg × 10 days, i.p.). Data are represented as mean ± S.D. nmol of epoxide formed/mg of protein after 60-min incubations with 1 mM (R)-VCH or (S)-VCH (n = 3–4 in duplicate; mouse microsomes were prepared from four mice/group). Numbers in parentheses represent significant (p< 0.05) fold-increase in epoxide metabolite formation over control microsomal incubations with that particular enantiomer.
N.D., not detectable.
↵1-150 Significantly different amount of epoxide formation from (S)-VCH in the same species and treatment group, atp < 0.05.