Cytochromes P450 alterations

Atkins, W.M. and S.G. Sligar (1989). Molecular recognition in cytochrome P450— alteration of regioselective alkane hydroxylation via protein engineering. J. Am. Chem. Soc. Ill, 2715-2717. 

Some of the causes of hepatotoxicity outlined by Lee (2003) include covalent binding of xenobiotics mediated by cytochrome P450s alterations of mitochondrial function affecting beta-oxidation of fatty acids ... 

Cosme J, Johnson EF. Engineering microsomal cytochrome P450 2C5 to be a soluble, monomeric enzyme. Mutations that alter aggregation, phospholipid dependence of catalysis, and membrane binding. /FtoZ Chem 2000 275 2545-53. 

Schuetz EG, Umbenhauer DR, Yasuda K, Brimer C, Nguyen L, Reeling MV. Altered expression of hepatic cytochromes P450 in mice deficient in one or more mdrl genes. Mol Pharmacol 2000 57 188-197. 

Ropinirole is initiated at 0.25 mg three times daily and increased by 0.25 mg three times daily on a weekly basis to a maximum of 24 mg/day. It is metabolized by cytochrome P450 1A2 fluoroquinolones and smoking may alter ropinirole clearance. 

CKD may alter nonrenal clearance of drugs as the result of changes in cytochrome P450-mediated metabolism in the hver and other organs. The clinical reductions in nonrenal clearance in CKD are generally proportional to the reductions in glomerular filtration rate (Table 77-1). 

The selective monohydroxylation of heterocyclic compounds such as piperidine derivatives1741 and the 7-lactam (19)[751 have been studied. It is also been shown that hydroxylation of phenylcyclohexane can be effected using cytochrome P450 and the regioselectivity of hydroxylation can be altered by site-directed mutagenesis of the enzyme1761. 

Crespi, C.L. and Miller, V.P. (1997) The R144C change in the CYP2C9 2 allele alters interaction ofthe cytochrome P450 with NADPH cytochrome P450 oxidoreductase. Pharmacogenetics, 7 (3), 203-210. 

In the liver s hepatocytes, the proportion represented by the sER is particularly high. It contains enzymes that catalyze so-called biotransformations. These are reactions in which apolar foreign substances, as well as endogenous substances—e. g., steroid hormones—are chemically altered in order to inactivate them and/or prepare them for conjugation with polar substances (phase I reactions see p. 316). Numerous cytochrome P450 enzymes are involved in these conversions (see p. 318) and can therefore be regarded as the major molecules of the sER. 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

The kidneys are susceptible to toxicity from xenobiotics (Fig. 7.1) because they too have a high blood flow. Cells of the tubular nephron face double-sided exposure, to agents in the blood on the basolateral side and in the Altered urine on the luminal side. Proximal tubule cells are generally the site of nephrotoxicity, since these cells have an abundance of cytochrome P450 and can transport organic anions and cations from the blood into the cells, thereby concentrating these chemicals manyfold. 

Cytochrome P450 2D6 and 3A4 activities. Saw palmetto extract, administered to healthy volunteers (six men and six women) for 14 days at generally recommended doses, did not alter the disposition of coadministered dextromethorphan and alprazolam primarily dependent on the CYP2D6 or CYP3A4 pathways for elimination b Cytotoxic activity. Extract from saw palmetto, in LNCaP cell culture, produced cell... 

Devane, et al. Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers. Clin Pharmacol Ther 2003 74(6) 536-542. 

Galantamine is metabolized primarily by CYP 2D6 and 3A4, and levels may be altered by inducers or inhibitors of these enzymes. Galantamine has not been shown to inhibit major cytochrome P450 enzymes. However, the pharmacodynamic interactions associated with other cholinesterase inhibitors may occur. 

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