Liver cytochrome P450 hydroxylation

Distlerath, L. M., Reilly, E E, B., Martin, M. V Wilkinson, G. R., and Guengerich, E E (1985). Immunochemical Characterization of the Human Liver Cytochrome P450 Involved in Debrisoquine Hydroxylation, In Microsomes and Drug Oxidations (A. R. Boobis, J. Caldwell, E De Matters, and C. R, Elcombe, eds.), Taylor Francis, London, pp. 380-389. 

Wrighton, S.A., J.C. Stevens, G.W. Becker, and M. VandenBranden (1993). Isolation and characterization of human liver cytochrome P450 2C19 Correlation between 2C19 and 5-mephenytoin 4 -hydroxylation. Arch. Biochem. Biophys. 306, 240-245. 

Yamazaki, H. and T. Shimada (1997). Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and 5-warfarin enantiomers. Biochem. Pharmacol. 54, 1195-1203. 

Distlerath LM, Reilly PEB, Martin MV, Davis GG, Wilkinson GR, Guengerieh FP. Purification and characterization of the human liver cytochromes P450 involved in debrisoquine 4-hydroxylation and phenaeetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J Biol Chem 1985 260 9057 9067. 

Yun CH, Shimada T, Guengerich FP (1992) Roles of human liver cytochrome P450 2C and 3A enzymes in the 3-hydroxylation of benzo[a]pyrene. Cancer Res 52 1868-1874... 

Y., Fujii, L.O.T., Miyazaki, H., and Inaba, T. (1998) N-Dealkylation and hydroxylation of ebastine by human liver cytochrome P450. Drug Metab. Dispos., 26 (6), 566-571. 

More recently, an indirect method of electrochemical detoxification of organisms has been put into practice. It is based on a model of the detoxifying function of the liver. A normal liver produces cytochrome P450, which assures the hydroxylation... 

Circulating melatonin is metabolized mainly in the liver, where it is first hydroxylated in the C6-position by cytochrome P450 monooxygenases (isoenzymes... 

The precursor, 7-dehydrocholesterol is converted by a non-enzymatic reaction to cholecalciferol (calciol). This reaction occurs in skin exposed to sunlight due to irradiation by UV-B light at a wavelength of about 300 nm. Cholecalciferol is transported via carrier proteins to the liver where hydroxylation at carbon-25 occurs in a reaction catalysed by a microsomal cytochrome P450 hydroxylase to form calcidiol. This compound travels to the kidney attached to specific binding proteins, where another cytochrome P450 enzyme, mitochondrial 1-a-hydroxylase, introduces a second hydroxyl group in to the molecule to form the active calcitriol. 

Axen E, Postlind H, Sjoberg H, Wikvall K. 1994. Liver mitochondrial cytochrome P450 CYP27 and recombinant-expressed human CYP27 catalyze 1 alpha-hydroxylation... 

Bylund J, Kunz T, Valmsen K, Oliw EH. 1998. Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes. J Pharmacol Exp Ther 284 51-60. 

Zafirlukast is extensively metabolized. Urinary excretion accounts for about 10% of the dose and the remainder is excreted in the feces. Liver microsomes that hydroxylate metabolites of zafirlukast are formed through the cytochrome P450 2C9 (CYP2C9) enzyme pathway. 

CYP2A6 (cytochrome P450 2A6) has been purified from human liver and CYP2A6 cDNA expression systems are available. Many studies have demonstrated marked interindividual variation in the levels of hepatic CYP2A6 protein, mRNA and associated microsomal coumarin 7-hydroxylase activity (reviewed in Pelkonen et al., 1997 Lake, 1999). The role of CYP2A6 in the metabolism of coumarin by human liver microsomes has been confirmed by Sai et al. (1999), who found that a monoclonal antibody to CYP2A6 inhibited coumarin 7-hydroxylation by more than 94%. 

The metabolism of 7V-nitrosodiethanolamine by a-hydroxylation, which is a cytochrome P450 (CYP)-mediated pathway, was not detected in liver preparations from uninduced male Fischer 344 rats (Farrelly et al., 1984,1987). The existence of a-hydroxylation was proved later, notably by the formation of glycol aldehyde in liver microsomes from rats pretreated with CYP2E1 inducers. The microsomal metabolism of N-nitrosodiethanolamine was slower by a-oxidation than by [3-oxidation (Loeppky, 1999). Bioactivation tests of jV-nitrosodiethanolamine in V79 Chinese hamster cells showed that cytotoxicity was observed only in cells transfected with human CYP2E1 but not in cells expressing CYP2B1 or in the controls (Janzowski et al., 1996 Loeppky, 1999). 

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