Monooxygenases Cytochrome P450 system

Most oxidation reactions are catalyzed by cytochrome P450 systems (see p. 318). These monooxygenases are induced by their substrates and show wide specificity. The substrate-specific enzymes of the steroid metabolism (see p. 376) are exceptions to this. 

Fumes B, Schlenk D. Extrahepatic metabolism of carbamate and organophosphate thioether compounds by the flavin-containing monooxygenase and cytochrome P450 systems. Drug Metab Dispos 2005 33 214—218. 

Low et al. (2004) have proposed a model to explain thioacetamide-induced hepatotox-icity and cirrhosis in rat livers. The pathways of thioacetamide-induced liver fibrosis were found to be initiated by thioacetamide S-oxide derived from the biotransformation of thioacetamide by the microsomal flavin-adenine nucleotide containing monooxygenase and cytochrome P450 systems and involve oxidative stress and depletion of succinyl-CoA, thus affecting heme and iron metabolism. Karabay et al. (2005) observed such hepatic damage in rats with elevation of total nitrite level in livers and decrease in arginase activity. The authors have reported that nitrosative stress was essentially the critical factor in thioacetamide-induced hepatic failure in rats. 

Scheme 10.3 Electron-transport systems associated with cytochrome P450 monooxygenases. Arrows indicate electron transfer.

The microsomal fraction consists mainly of vesicles (microsomes) derived from the endoplasmic reticulum (smooth and rough). It contains cytochrome P450 and NADPH/cytochrome P450 reductase (collectively the microsomal monooxygenase system), carboxylesterases, A-esterases, epoxide hydrolases, glucuronyl transferases, and other enzymes that metabolize xenobiotics. The 105,000 g supernatant contains soluble enzymes such as glutathione-5-trans-ferases, sulfotransferases, and certain esterases. The 11,000 g supernatant contains all of the types of enzyme listed earlier. 

Monooxygenases (MOs) Enzyme systems of the endoplasmic reticulum of many cell types, which can catalyze the oxidation of a great diversity of lipophilic xenobiotics, are particularly well developed in hepatocytes. Forms of cytochrome P450 constitute the catalytic centers of monooxygenases. 

Boon, J.P., Van Arnhem, E., and Jansen, S. et al. (1992). The toxicokinetics of PCBs in marine mammals with special reference to possible interactions of individual congeners with cytochrome P450 dependent monooxygenase systems an overview. In C.H Walker and D. Livingstone (1992). Persistent Pollutants in Marine Ecosystems 119-160. 

Fent, K., Woodin, B.R., and Stegeman, J.J. (1998). Effects of triphenyl tin and other organotins on hepatic monooxygenase system in fish. In D.R. Livingstone and J.J. Stegeman (Eds.) Forms and Functions of Cytochrome P450, 277-288. 

H)2-D3 is a weak agonist and must be modified by hydroxylation at position Cj for full biologic activity. This is accomplished in mitochondria of the renal proximal convoluted tubule by a three-component monooxygenase reaction that requires NADPFl, Mg, molecular oxygen, and at least three enzymes (1) a flavoprotein, renal ferredoxin reductase (2) an iron sulfur protein, renal ferredoxin and (3) cytochrome P450. This system produces l,25(OH)2-D3, which is the most potent namrally occurring metabolite of vitamin D. 

Cytochrome P450-type monooxygenase systems, which have a generally low substrate specificity, are widely distributed in the species of fish used for toxicity testing (Funari et al. 1987). 

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