Abstract

Although CYP2B6 catalyzes the biotransformation of many drugs used clinically in children and adults, information regarding the effects of development on CYP2B6 expression and activity are scarce. Utilizing a large panel of human liver samples (201 donors: 24 fetal, 141 pediatric and 36 adult), we quantified CYP2B6 mRNA and protein expression levels, characterized CYP2B6 (bupropion hydroxylase) activity in human liver microsomes (HLMs) and performed an extensive genotype analysis to differentiate CYP2B6 haplotypes so that the impact of genetic variation on these parameters could be assessed. Fetal livers contained extremely low levels of CYP2B6 mRNA relative to post-natal samples and all of the fetal HLMs failed to catalyze bupropion hydroxylation, but fetal CYP2B6 protein levels were not significantly different from post-natal levels. Considerable inter-individual variation in CYP2B6 mRNA expression, protein levels and activity was observed in post-natal HLMs (mRNA, ~40,000-fold; protein, ~300-fold; activity, ~600-fold). The extremely wide range of inter-individual variability in CYP2B6 expression and activity was significantly associated with age (ρ<0.01) following log transformation of the data. Our data suggest that CYP2B6 activity appears as early as the first day of life, increases through infancy, and by 1 year of age, CYP2B6 levels and activity may approach those of adults. Surprisingly, CYP2B6 inter-individual variability was not significantly associated with genetic variation in CYP2B6, nor with differences in gender or ethnicity, suggesting that factors other than these are largely responsible for the wide range of variability in CYP2B6 expression and activity observed among a large group of individuals/samples.