Akiko Kawaji

Hepatic cytochrome P450 and flavin-containing monooxygenase in male Nts:Mini rat, a transgenic rat carrying antisense RNA transgene for rat growth hormone.

We investigated the characteristics of hepatic cytochrome P450s and flavin-containing monooxygenase 1 (FMO1) in male Nts:Mini rats, a Wistar/Jcl-derived transgenic rat strain showing less plasma GH concentration than the parental strain. The total hepatic P450 contents of Mini rats were significantly reduced. A suppression was observed in the activities and protein expression of male-specific P450s (CYP3A and CYP2C11) and was speculated to be a potential cause of the reduction in total P450 contents. The activity and protein expression of CYP2B1 were suppressed and those of CYP2E1 and CYP2B2 were enhanced. With the exception of our data on CYP2B1, these results largely agreed with previous reports concerning GH-depletion rat models (hypophysectomized rats, rats neonatally treated with glutamate, and dwarf rats), implying that the changes in Mini rats were caused by GH insufficiency. The liver FMO1 protein expression in Mini rats was higher than that in Wistar rats but the activity was comparable, suggesting that GH is not a positive regulator of FMO expression. With their insufficient but not depleted levels of plasma GH, Mini rats may thus become another candidate for use in the investigation of GH regulation of hepatic mixed-function monooxygenases.

Flavin-containing monooxygenase mediated metabolism of benzydamine in perfused brain and liver

Benzydamine (BZY) N-oxidation mediated by flavin-containing monooxygenase (FMO) was evaluated in perfused brain and liver. Following 20 min of perfusion with modified Ringer solution, the infusion of BZY into brain or liver led to production of BZY N-oxide. BZY N-oxide, a metabolite of BZY oxidized exclusively by FMO, was mostly recovered in the effluent without undergoing further metabolism or reduction back to the parent substrate. The BZY N-oxide formation rate increased as the infusion concentration of BZY increased both in perfused brain and perfused liver. BZY N-oxidation activities in perfused rat brain and liver were 4.2 nmol/g brain/min and 50 nmol/g liver/min, respectively, although the BZY N-oxidation activity in brain homogenates was one 4000th that in liver homogenates. This is the first study of FMO activity in brain in situ.