Tissue-specific expression of flavin-containing monooxygenase (FMO) forms 1 and 2 in the rabbit

The microsomal flavin-containing monooxygenases (FMO) represent a family of xenobiotic-metabolizing enzymes with distinct tissue- and species-specific patterns of expression. Expression for two FMO isoforms (FMO1 and FMO2) in rabbit was characterized by determining mRNA levels, protein levels and catalytic activity in male and female liver, lung, kidney, esophagus, intestine, nasal mucosa (maxilloturbinates and ethmoturbinates) and gonadal tissue. Northern blot hybridization analyses performed with cDNA probes for each isoform showed marked differences in mRNA expression between tissues: FMO1 expression was highest in liver and intestine, followed by ethmoturbinates, maxilloturbinates and low but detectable levels in female kidney; FMO2 expression was highest in lung, followed by maxilloturbinates, ethmoturbinates, esophagus and kidney. More sex-related differences were observed for FMO2, with higher levels of mRNA in female esophagus, nasal mucosa and kidney. Western blot analyses showed similar patterns of expression at the protein level. Microsomal catalytic activities determined by [14C]-DMA N-oxide formation also indicated tissue- and sex-related differences in substrate metabolism by FMO. Analysis of tissue-specific FMO catalytic activity was also performed using thiocarbamides as isoform-specific probes. Microsomes from those tissues containing FMO2, but not FMO1, failed to catalyze oxidation of the larger (van der Waals surface area greater than 178 A) FMO1-specific thiocarbamides. The results of this study demonstrate that tissue-specific control mechanisms play a more dominant role in the overall constitutive regulation of FMO than other potential factors, such as hormonal influences. Elucidation of the mechanisms controlling FMO tissue-specific expression will lead to a better understanding of target organ specificity for xenobiotic detoxication or bioactivation.