P450 cytochrome xenobiotic metabolism

Biological Models for Studying Function of Respiratory Tract Cytochromes P450 in Xenobiotic Metabolism and Chemical Toxicity... 

Xenobiotics metabolism, 1, 223-225 monooxygenation cytochrome P450 in, 1, 259-260 Xenon... 

Yang CS, Brady JF, Hong JY Dietary effects on cytochromes P450, xenobiotic metabolism, and toxicity. FASEB J 1992 6 737. 

Hakkola, J., Pasanen, M., Purkunen, R., Saarikoski, S., Pelkonen, O., Maenpaa, J., Rane, A. and Raunio, H. (1994) Expression of xenobiotic-metabolizing cytochrome P450 forms in human adult and fetal liver. Biochemical Pharmacology, 48 (1), 59-64. 

L. W. Wormhoudt, J. N. Commandeur, N. P. Vermeulen, Genetic Polymorphisms of Human V-Acetyltransferase, Cytochrome P450, Glutathione 5-Transferase, and Epoxide Hydrolase Enzymes Relevance to Xenobiotic Metabolism and Toxicity , Crit. Rev. Toxicol. 1999, 29, 59 - 124. 

A striking feature of the collection of human brain cytochrome P450s discussed in the present review is the obvious major classes they fall into. With the exception of CYP26A1, which appears to be alone in the retinoic acid metabolic pathway, all the other brain P450s, including those normally considered xenobiotic-metabolizing, are either involved in the metabolism (or synthesis, in the case of CYP51, the... 

Bhagwat SV, Boyd MR, Ravindranath V. 1995a. Brain mitochondrial cytochromes P450 xenobiotic metabolism, presence of multiple forms and their selective inducibility. Arch Biochem Biophys 320 73-83. 

Johri A, Dhawan A, Lakhan Singh R, Parmar D. 2006. Effect of prenatal exposure of deltamethrin on the ontogeny of xenobiotic metabolizing cytochrome P450s in the brain and liver of offsprings. Toxicol Appl Pharmacol 214 ... 

Lewis, D. F. V. (1999) Homology modelling of human cytochromes P450 involved in xenobiotic metabolism and rationalization of substrate selectivity. Exp. Toxicol. Pathol. 51, 369-374. 

The lowest dose effects of diuron are seen at 0.27 mg kg-1 per day. Almost all of the low-dose expression changes are related to genes involved with xenobiotic metabolism and transport, including cytochrome P450 enzymes and several transferases. These data indicate that the cells are responding appropriately to a potentially toxic xenobiotic. These effects are widespread across the set of chemicals tested in ToxCast, so it is of interest that 2,4-D does not trigger a similar xenobiotic metabolism response. 

The cytochrome P450 system is the principal enzyme system for the metabolism of lipophilic xenobiotics. It is a heme-containing, membrane-bound, multi-enzyme system which is present in many tissues in vivo but is present at the highest level in liver. A coenzyme, cytochrome P450 NADPH oxidoreductase (OR), is essential for P450 catalytic function and cytochrome bs may stimulate catalytic activities of some enzymes. In human liver, it is estimated that there are 15-20 different xenobiotic-metabolizing cytochrome P450 forms. A standard nomenclature, based on relatedness of the amino acid sequences, has been developed (Nelson et al., 1993). The most recent... 

In vitro systems containing human xenobiotic-metabolizing enzymes can provide qualitative data, such as the human metabolites which may be produced in vivo and which enzymes are capable of producing these metabolites. When comparing quantitative aspects of metabolism among different cytochrome P450 forms in a cDNA expression system, the data can be interpreted in two contexts ... 

The field of xenobiotic metabolism is rich with a myriad of different, often competing, pathways of metabolism. Efforts at cDNA expression have only begun to develop comprehensive systems for the analysis of all Phase I and all Phase II enzymes. A comprehensive set of human cytochrome P450 and Phase II enzymes is not available in the context of a single host cell type, but given the rate of progress, we can look forward to nearly complete systems in the near future. 

Ding X, Kaminsky LS. Human extrahepatic cytochromes P450 function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol 2003 43 149-173. 

Inhibitory antibodies are frequently used in studies of xenobiotic metabolism, usually to estimate the contribution of particular enzymes in multienzyme mixtures. An important example is the use of antibodies to estimate the contribution of individual cytochrome P450 isoforms to the overall metabolism of a xenobiotic in microsomal preparations. 

Whereas most, if not all, of the enzymes involved in xenobiotic metabolism can form reactive metabolites (Table 8.1), the enzyme systems most frequently involved in the activation of xenobiotics are those which catalyze oxidation reactions. The cytochrome P450 monooxygenases (CYP) are by far the most important enzymes involved in the oxidation of xenobiotics. This is because of the abundance of CYP (especially in the liver), the numerous isozymes of CYP, and the ability of CYP to be induced by xenobiotic compounds. 

Comparative biochemistry. Some researchers believe that the proper role of comparative biochemistry is to put evolution on a molecular basis, and that detoxication enzymes, like other enzymes, are suitable subjects for study. Xenobiotic-metabolizing enzymes were probably essential in the early stages of animal evolution because secondary plant products, even those of low toxicity, are frequently lipophilic and as a consequence would, in the absence of such enzymes, accumulate in lipid membranes and lipid depots. The evolution of cytochrome P450 isoforms, with more than 2000 isoform cDNA sequences known, is proving a useful tool for the study of biochemical evolution. 

These reactive metabolites can bind covalently to cellular macromolecules such as nucleic acids, proteins, cofactors, lipids, and polysaccharides, thereby changing their biologic properties. The liver is particularly vulnerable to toxicity produced by reactive metabolites because it is the major site of xenobiotic metabolism. Most activation reactions are catalyzed by the cytochrome P450 enzymes, and agents that induce these enzymes, such as phenobarbital and 3-methylcholanthrene, often increase toxicity. Conversely, inhibitors of cytochrome P450, such as SKF-525A and piperonyl butoxide, frequently decrease toxicity. 

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