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. 

Ketoconazole inhibits a variety of cytochrome P450 enzymes, including 11-hydroxylase and 17-hydroxylase. It is highly effective in lowering cortisol in Cushing s disease, and patients can be maintained successfully on therapy for months to years. The most common adverse effects are reversible elevation of hepatic transaminases and GI upset. It can cause gynecomastia and lower plasma testosterone values. 

Park, B.K., Pirmohamed, M., and Kitteringham, N.R., The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity, Pharmac. Then 68, 385, 1995. 

Harris, J.W., Rahman, A., Kim, B.R., Guengerich, F.P. and Collins, J.M. (1994) Metabolism of taxol by human hepatic microsomes and liver slices participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Research, 54 (15), 4026-4035. 

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... 

An alternative approach to relying simply upon allometric approaches for metaboli-cally-cleared compounds is to take into consideration their relative stability in vitro. Clearance by P450 enzymes observed in hepatic microsomes from different species provides a measure of the relative intrinsic clearance in different species. Using the equation for the well-stirred model ... 

Generally, the liver is the center of drug metabolism, hence numerous drugs and methods to measure functional hepatic capacity are available. A host of these methods rely on the metabolic activity of cytochrome P450 enzymes, and some of the markers used include phenacetin, methacetin, trimethadione. 

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...

There is heterogeneity in human populations for the hepatic microsomal cytochrome P450 enzyme (see Chapter 4). Possession of an unfavorable phenotype may place a patient at risk for drug toxicity. For exam-... 

Rifapentine is an analogue of rifampin that is active against M. tuberculosis and M. avium. Rifapentine s mechanism of action, cross-resistance, hepatic induction of P450 enzymes, drug interactions, and toxic profile are similar to those of rifampin. It has been used in the treatment of tuberculosis caused by rifampin-susceptible strains. 

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). 

---