TISSUE-SPECIFIC EXPRESSION OF FLAVIN-CONTAINING MONOOXYGENASE (FMO) FORM-1 AND FORM-2 IN THE RABBIT

The microsomal flavin-containing monooxygenases (FMO) represent a fami ly of xenobiotic-metabolizing enzymes with distinct tissue- and specie s-specific patterns of expression. Expression for two FMO isoforms (FM O1 and FMO2) in rabbit was characterized by determining mRNA levels, p rotein levels and catalytic activity in male and female liver, lung, k idney, esophagus, intestine, nasal mucosa (maxilloturbinates and ethmo turbinates) and gonadal tissue. Northern blot hybridization analyses p erformed with cDNA probes for each isoform showed marked differences i n mRNA expression between tissues: FMO1 expression was highest in live r and intestine, followed by ethmoturbinates, maxilloturbinates and lo w 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 hig her levels of mRNA in female esophagus, nasal mucosa and kidney. Weste rn blot analyses showed similar patterns of expression at the protein level. Microsomal catalytic activities determined by [C-14]-DMA N-oxid e formation also indicated tissue- and sex-related differences in subs trate metabolism by FMO. Analysis of tissue-specific FMO catalytic act ivity was also performed using thiocarbamides as isoform-specific prob es. Microsomes from those tissues containing FMO2, but not FMO1, faile d to catalyze oxidation of the larger (van der Waals surface area grea ter than 178 Angstrom) FMO1-specific thiocarbamides. The results of th is study demonstrate that tissue-specific control mechanisms play a mo re dominant role in the overall constitutive regulation of FMO than ot her 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 detoxi cation or bioactivation.