Relative expression of cytochrome P450 isoenzymes in human liver and association with the metabolism of drugs and xenobiotics

Abstract

Cytochrome P450s play a central role in the metabolism and disposition of an extremely wide range of drugs and chemical carcinogens. Individual differences in the expression of these enzymes may be an important determinant in susceptibility to adverse drug reactions, chemical toxins and mutagens. In this paper, we have measured the relative levels of expression of cytochrome P450 isoenzymes from eight gene families or subfamilies in a panel of twelve human liver samples in order to determine the individuality in their expression and whether any forms are co-regulated. Isoenzymes were identified in most cases on Western blots based on the mobility of authentic recombinant human cytochrome P450 standards. The levels of the following P450 proteins correlated with each other: CYP2A6, CYP2B6 and a protein from the CYP2C gene subfamily, CYP2E1 and a member of the CYP2A gene subfamily, CYP2C8, CYP3A3/A4 and total cytochrome P450 content. Also, the levels of two proteins in the CYP4A gene subfamily were highly correlated. These correlations are consistent with the relative regulation of members of these gene families in rats or mice. In addition, the level of expression of specific isoenzymes has also been compared with the rate of metabolism of a panel of drugs, carcinogens and model P450 substrates. These latter studies demonstrate and confirm that the correlations obtained in this manner represent a powerful approach towards the assignment of the metabolism of substrates by specific human P450 isoenzymes.

Genetic Clamping of Renin Gene Expression Induces Hypertension and Elevation of Intrarenal Ang II Levels of Graded Severity in Cyp1a1-Ren2 Transgenic Rats

“…However, a number of studies utilising various experimental models of Ang II-dependent hypertension, including two-kidney, one-clip (2K1C) Goldblatt hypertensive rats, Ang II-infused hypertensive rats, and TGR(mRen2)27 transgenic rats, have clearly demonstrated that intrarenal levels of Ang II can be dissociated from both circulating Ang II concentrations and kidney renin content. [10][11][12][13][14][15][16] Indeed, Ang II contents in the non-clipped kidney of 2K1C Goldblatt hypertensive rats and in kidneys from Ang II-infused rats and hypertensive TGR(mRen2)27 transgenic rats are higher than can be explained on the basis of circulating Ang II levels even though these kidneys are markedly renin-depleted. [10][11][12][13][14][15][16] In the Ang II-infused hypertensive rat, chronic administration of an AT 1 -receptor antagonist prevents the hypertension and the associated increase in intrarenal Ang II levels, 13,17,18 suggesting that in this hypertensive model the augmentation if intrarenal Ang II levels is mediated in part by AT 1 -receptor-mediated uptake of Ang II.…”

“…9 This transgenic rat line (strain name: TGR[Cyp1a1-Ren2]) was created by inserting the mouse Ren2 renin gene, fused to an 11.5 kb fragment of the cytochrome P450 1a1 (Cyp1a1) promoter, into the genome of the Fischer 344 rat. 9 Cyp1a1, which catalyses the oxidation of a wide range of endogenous lipophilic compounds and xenobiotics, [10][11][12] is not constitutively expressed, but is highly inducible upon exposure to various aryl hydrocarbons such as indole-3-carbinol (I3C). [10][11][12][13][14][15][16] Induction of Cyp1a1 is mediated by the aryl hydrocarbon receptor, which is a basic helix-loophelix-transcription factor that binds to specific DNA elements in the Cyp1a1 promoter.…”

“…9 Cyp1a1, which catalyses the oxidation of a wide range of endogenous lipophilic compounds and xenobiotics, [10][11][12] is not constitutively expressed, but is highly inducible upon exposure to various aryl hydrocarbons such as indole-3-carbinol (I3C). [10][11][12][13][14][15][16] Induction of Cyp1a1 is mediated by the aryl hydrocarbon receptor, which is a basic helix-loophelix-transcription factor that binds to specific DNA elements in the Cyp1a1 promoter. 10,12,17 Rats transgenic for the Cyp1a1-Ren2 construct do not constitutively express the Ren2 renin gene.…”

Anticarcinogenic Factors in Plant Foods: A New Class of Nutrients?

“…There are many examples of drugs and xenobiotics (Forrester et al 1992), including caffeine (Gandhi & Khanduja, 1992) and ethanol (Lucas et al 1992), which increase some P450 involved in phase I metabolism. Other non-nutrient components of human foods which have been shown to have this effect include the flavonoids tangeretin, flavone and nobiletin .…”

An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems.

“…The metabolism of halofantrine by CYP3A therefore implies that, the interindividual variation in the activity of this enzyme in both the liver and gut wall [42,43], and also variation caused by enzyme induction or enzyme inhibition [44,45], may contribute to the known variable disposition of the drug. In contrast, it is unlikely that CYP2D6 genotype will be a major determinant of halofantrine disposition.…”