Cytochrome P450 enzymes induction

The traditional approach for assessing hepatotoxicity integrates clinical chemistry markers, histopathology evaluation, cytochrome P450 enzyme induction, in-life... 

Oxcarbazepine is a keto derivative of carbamazepine but offers several advantages over carbamazepine. Oxcarbazepine does not require blood cell count, hepatic, or serum drug level monitoring. It causes less cytochrome P450 enzyme induction than does carbamazepine (but may decrease effectiveness of oral contraceptives containing ethinyl estradiol and levonorgestrel). As opposed to carbamazepine, oxcarbazepine does not induce its own metabolism. These properties, combined with its similarity to carbamazepine, led many clinicians to use this medication for the treatment of bipolar disorder. Randomized controlled trials suggested efficacy in the treatment of acute mania compared with lithium and haloperidol, but these trials were quite small and did not include a placebo control (Emrich 1990). 

Uncertain. Atovaquone is predominantly excreted (greater than 90%) as unchanged drug in the faeces, - and would not therefore be expected to be alfected by cytochrome P450 enzyme induction. 

Liu, C., Russell, R.M., and Wang, X.D., Exposing ferrets to cigarette smoke and a pharmacological dose of beta-carotene supplementation enhance in vitro retinoic acid catabolism in lungs via induction of cytochrome P450 enzymes, J. Nutr., 133, 173, 2003. 

Paolini, M., Antelli, A., Pozzetti, L. et al. 2001. Induction of cytochrome P450 enzymes and over-generation of oxygen radicals in beta-carotene supplemented rats. Carcinogenesis 22 1483-1495. 

Lin, J.H. and Lu, A.Y. (2001) Interindividual variability in inhibition and induction of cytochrome P450 enzymes. Annual Review of Pharmacology and Toxicology, 41, 535—567. 

J. K. Doerr-Stevens, J. Liu, G. J. Stevens, J. C. Kraner, S. M. Fontaine, J. R. Halpert, I. G. Sipes, Induction of Cytochrome P450 Enzymes after Repeated Exposure to 4-Vinyl-cyclohexene in B6C3F1 Mice , Drug Metab. Dispos. 1999, 27, 281 - 287. 

Westerink, W.M.A. and Schoonen, W.G.E.J. (2007) Cytochrome P450 enzyme levels in HepG2 cells and cryopreserved primary human hepatocytes and their induction in HepG2 cells. Toxicology In Vitro, 21, 1581-1591. 

For halogenated aromatic hydrocarbons like polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo-p-dioxins (PCDDs) the binding to the aryl hydrocarbon (Ah) receptor regulates their toxicity [89]. The Ah receptor controls the induction of one of the cytochrome P450 enzymes in the liver. Toxic responses such as thymic atrophy, iveight loss, immu-notoxicity and acute lethality are associated ivith the relative affinity of PCBs, PCDFs and PCDDs for the Ah receptor [89]. The quantitative structure-activity relationship (QSAR) models predicting the affinity of the halogenated aromatic hydrocarbons ivith the Ah receptor describe the electron acceptor capability as well as the hydrophobicity and polarizability of the chemicals [89[. 

St. John s wort is probably effective for mild to moderate but not severe depression. Although well tolerated in most patients, a major concern is its numerous herb-drug interactions mediated by its induction of the cytochrome P450 enzyme system. 

In addition, many of the cytochrome P450 enzymes can be induced. Induction causes the liver to produce a greater amount of the enzyme, which can increase elimination and reduce plasma levels... 

Drugs can not only be substrates for a cytochrome P450 enzyme or an inhibitor of a P450 enzyme, they can also be inducers of a cytochrome P450 enzyme and thereby increase the activity of that enzyme. This was discussed in Chapter 6 for CYP450 3A4, and the induction of 3A4 activity by the anticonvulsant and mood stabilizer carbamazepine was given as an example (Fig. 6—19). Since mood stabilizers may be frequently mixed with atypical antipsychotics, it is possible that carbamazepine may be added to the regimen of a patient previously stabilized on clozapine, quetiapine, ziprasidone, or sertindole. If so, the doses of these atypical antipsychotics may need to be increased over time to compensate for the induction of 3A4 by carbamazepine. 

Robertson P, DeCory HH, Madan A, Parkinson A (2000) in vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. Drug Metab Dispos 28 664— 671... 

In Vitro Models for Studying Induction of Cytochrome P450 Enzymes... 

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