Cytochrome P450 enzymes, hepatic

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes... 

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes. Figure 1 General mechanism for transcriptional activation of CYP genes by xenochemicals that activate their cognate xeno-receptor proteins. In the case of Ah receptor, the receptor s heterodimerization partner is Arnt, whereas in the case of the nuclear receptors CAR, PXR, and PPARa, the heterodimerization partner is RXR. The coactivator and basal transcription factor complexes shown are each comprised of a large number of protein components. 

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

Blus, L.J., M.J. Melancon, D.J. Hoffman, and C.J. Henny. 1998. Contaminants in eggs of colonial waterbirds and hepatic cytochrome P450 enzyme levels in pipped tem embryos, Washington State. Arch, Environ. Contam. Toxicol. 35 492-497. 

Lehman-McKeeman ED, Caudill D, Vassallo JD, Pearce RE, Madan A, Parkinson A (1999) Effects of musk xylene and musk ketone on rat hepatic cytochrome P450 enzymes. Toxicol Lett 111 105-115... 

Metabolism - In vitro studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. P.982... 

Table 5 SSRIs and hepatic cytochrome P450 enzymes...

Interferons reduce the activity of hepatic cytochrome P450 enzymes and decrease the clearance of drugs such as theophylline. Their effects may be additive with other drugs that have neurotoxic, hematotoxic or cardiotoxic activity. 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

Mirtazapine does not significantly inhibit hepatic cytochrome P450 enzymes. Additive effects may occur when mirtazapine is combined with other drugs with sedative or vascular effects. Mirtazapine should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. When it is combined with fluvoxamine, a potent inhibitor of P450 enzymes— including 1A2, 2D6, and 3A4, which metabolizes mirtazapine—the plasma concentration of mirtazapine may be increased by up to fourfold (AnttUa et al. 2001 Demers et al. 2001). 

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... 

Reimann G, Barthel B, Rockstroh JK, Spatz D, Brockmeyer NH. Effect of fusidic acid on the hepatic cytochrome P450 enzyme system. Int J Clin Pharmacol Ther 1999 37(ll) 562-6. 

Figure 4.1 (a) Hormone nuclear receptors involved in the regulation of hepatic cytochrome P450 enzymes, phase II conjugation enzymes, and uptake/efflux transporters. (,b) Integrated regulation of phase I and II enzymes as well as uptake and efflux proteins by nuclear receptors. (Modified from [98].)... 

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