DEVELOPMENTAL REGULATION OF FLAVIN-CONTAINING MONOOXYGENASE (FMO) ISOFORM-1 AND ISOFORM-2 IN PREGNANT RABBIT

Mammalian flavin-containing monooxygenase (FMO, EC 1.14.13.8) metaboli zes a vast number of structurally diverse xenobiotics containing a sof t-nucleophile, typically a nitrogen or sulfur. FMO is not inducible by the classical cytochrome P450 (CYP) inducers, such as phenobarbital, polycyclic aromatic hydrocarbons, ethanol or macrolide antibiotics. Ev idence does exist from a number of laboratories, however, for developm ental and hormonal regulation of FMO. Our laboratory has confirmed pre vious observations of enhanced FMO activity during mid- and late-gesta tion in maternal rabbit lung and have demonstrated that this response is due to increased protein and catalytic activity associated with FMO 2. The time course of expression of FMO2 during mid- and late-gestatio n correlates to plasma peaks of progesterone or cortisol. FMO2 also pe aks at parturition in maternal kidney, coincident with plasma cortisol levels. FMO2 is induced by s.c. administration of either progesterone or dexamethasone in lung, or by dexamethasone in kidney. Correlation of plasma progesterone or cortisol levels during gestation and postpar tum support a role for progesterone, but not cortisol in regulation of FMO2 in maternal rabbit lung, The levels of FMO1 also appear to be in creased during mid- and late-gestation in liver. FMO1 in liver may als o be regulated during gestation by progesterone or glucocorticoids as administration of these steroids enhanced FMO1 mRNA levels 4-fold.