Houseman, L.; (2008) Flavin-containing monooxygenases: regulation, endogenous roles and dietary supplements. Doctoral thesis , University of London.

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Abstract

To investigate the regulation of flavin-containing monooxygenase 5 (FM05) by xenobiotics in mouse liver, a method for isolating primary mouse hepatocytes was designed. Fmo5 expression was up-regulated by hormones (estradiol, progesterone), dietary supplements (lipoic acid) and other xenobiotics (rifampicin, ethanol) in primary mouse hepatocytes and HepG2 cells. Gene reporter assays showed that Fmo5 expression in HepG2 cells is mediated by pregnane-x-receptor (PXR) ligands. To uncover more about the endogenous role of FMOs, two knockout mouse models, Fmol, 2, 4 (-/-) and Fmo5 (-/-), were studied. Fmol, 2, 4 (-/-) males weighed less and had less gonadal fat than their wild-type counterparts. The bodyweight of the Fmol, 2, 4 (-/-) females was greater than that of the wild-type females. Histology shows that the adipocytes in the Fmol, 2, 4 (-/-) male mice are 50% smaller than wild-type male adipocytes, and the liver histology shows the Fmol, 2, 4 (-/-) males had less fat in the liver compared to wild-type males. Fmol, 2, 4 (-/-) mice had higher plasma total-, HDL- and LDL-cholesterol than the wild-type mice. On a high-fat diet, the male Fmol, 2, 4 (-/- ) mice gain weight and gonadal fat weight. The Fmo5 (-/-) mice have a similar bodyweight and fat weight to the wild-type animals, but Fmo5 (-/-) mice have lower plasma HDL cholesterol and lower plasma iron than WT mice. The results therefore show that a deficiency in FMOs interferes with endogenous fat metabolism. Lipoic acid is an endogenous substrate of FMOl, so to see if the inability to metabolise lipoic acid is the reason for the lower bodyweight and fat weight in Fmol, 2, 4 (-/-) males, the mice were fed a 0.1% lipoic acid diet. All knock-out and wild-type mice lose a similar amount of weight. This implies that the metabolism of lipoic acid is not the fundamental endogenous role of FMOs.

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