Human P450 Enzymes

Each of the 57 human P450s will be covered here. Clearly much more information is available about some than others. Points to be covered with each, when possible, include sites of expression and relative abundance, polymorphism and inducibility, substrates and reactions, knowledge of important residues and active site characteristics, inhibitors, and clinical issues. 

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Riley, R. et al., Human anti-endoplasmic reticulum autoantibodies produced in aromatic anticonvulsant hypersensitivity reactions recognize rodent C YP3 A proteins and a similarly regulated human P450 enzyme(s), Biochem. Biophys. Res. Commun., 191, 32, 1993. 

Human liver microsomes (HLMs) are the most common in vitro sources of enzymes for inhibition studies, and selective probe substrates are required. Recombinant human P450 enzymes have become commercially available. They are widely used for screening, and less selective probe substrate can be used. Hepatocytes and liver slices48 have also been used for P450 inhibition screening to a lesser extent. 

There are several examples in the literature of the integration of studies with cDNA-expressed human P450 enzymes and human liver microsomes which have led to improved understanding of human enzyme-mediated activation of protoxins. Some of these examples are discussed below. Most of these reports have taken a multifaceted approach combining studies in human liver microsomes with cDNA-expressed enzymes. The general metabolic properties of these toxic xenobiotics (e.g. multiplicity of enzymes, differences in affinity and capacity, methods to compare to human liver data, etc.) apply to drugs and drug candidates as well. 

Pearce RE, Rodrigues AD, Goldstein JA, et al. Identification of the human P450 enzymes involved in lasoprazole metabolism. J Pharmacol Exp Ther 1996 277 805-816. 

Table 3 summarizes typical incubation conditions and kinetic constants of marker substrate reactions of Human P450 enzymes in a pool of human liver microsomes (Mandan 2002). 

Henderson MC, Miranda CL, Stevens JF, Deinzer ML, Buhler DR. In vitro inhibition of human P450 enzymes by prenylated flavonoids from hops, Humulus lupulus. Xenobiotica 2000 30(3) 235-51. 

Donato MT, Jimenez N, Castell JV, et al. Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cells expressing individual human P450 enzymes. Drug Metab Disp. 2004 32 699-706. 

FIGURE 5.6 Biotransformation of VCV in HLM and cDNA-expressed human P450 enzymes. (Reprinted from Ghosal, A. et al., Drug Metab. Dispos., 35, 2186, 2007. With permission.)... 

Table 10.4. Some Human P450 Enzymes involved in the Activation of Carcinogens (See also Table 10.8)...

Table 10.6. Some Major Inducers of Human P450 Enzymes...

What is the capability of a human P450 enzyme to produce a given metabolite (including reactive intermediates) in vivo For examples, the... 

Fig. 9.1 The enzymes of drug metabolism, a Contribu- drug metabolism [49] (see also [50]). UGTUDG glueuro-tions of different enzymes to drug metabolism, b Con- nosyl transferase, FMO flavin-eontaining monoxygenase, tributions of individual human P450 enzymes to (P450) NATiV-aeetyltransferase, MAO monoamine oxidase...

Table 9.4 Some major inducers of human P450 enzymes ...

Table 9.8 Some human P450 enzymes involved in the activation of carcinogens [30, 99]. (See also Table 9.10 and Fig. 9.10). VO... 

Affinin inhibits the major human P450 enzymes involved in drug metabolism [179] and the NO production in a murine macrophage cell line, efficiently dowmegulates the production of inflammatory mediators IL-lp, IL-6, and TNF-a, and attenuates the expression of COX-2 and iNOS. These... 

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