Evidence for propofol hydroxylation by cytochrome P4502B11 in canine livermicrosomes: breed and gender differences

1. The study aimed to ascertain the enzyme kinetic basis for breed differen ces in the biotransformation of propofol in dog and to identify the respons ible canine cytochrome P450 (CYP) isoenzymes. 2. The NADPH-dependent formation of 4-hydroxypropofol (the rate-limiting bi otransformation in dog) was assayed using hepatic microsomes from the male greyhound and beagle, and from both sexes in mixed-breed dogs (five of each ). 3. Enzyme kinetic analysis revealed that whereas there were no significant differences in K-m, V-max averaged > 3-fold lower in greyhound compared wit h beagle (p = 0.032). Although average V-max was > 3-fold higher in the mal e compared with female mixed-breed dogs, this difference did not achieve st atistical significance (p = 0.095), probably because of the high variabilit y of data from mixed-breed dogs. 4. Chloramphenicol (a specific CYP2B11 inhibitor) and diethyldithiocarbamat e (a non-specific CYP2 inhibitor) inhibited propofol hydroxylation in all m icrosomes. Quinine (a CYP2D15 inhibitor) was also inhibitory, but only in o ne-half of the microsomes examined. Immune-inhibition by anti-CYP2B1 sera r esulted in > 50% reduction in metabolite formation in all dogs except mixed -breed females, which showed a 30% reduction. Differences in propofol hydro xylase activity between microsomal preparations were primarily attributed t o a component that was sensitive to inhibition by chloramphenicol and anti- CYP2B1 sera. 5. The results indicate that propofol hydroxylation in dog is primarily med iated by CYP2B11 and that breed (and possibly gender) differences in propof ol metabolism may result from differences in the liver content of this CYP.