Expression of Individual Metabolizing Enzymes

The catalytic activity of CYP enzymes requires functional coupling with its redox partners, cytochrome P450 NADPH oxidoreductase (OR) and cytochrome bs. Measurable levels of these two proteins are natively expressed in most cell lines. Therefore, introduction of only the CYP cDNA is generally needed for detectable catalytic activity. However, the levels of expression of the redox partner proteins may not support maximal CYP catalytic activity, and therefore enhancement of OR levels may be desirable. This approach has been used successfully with an adenovirus expression system in LLC-PKi cells [12], 

Systems to study the role of intestinal oxidative metabolism (CYP3A4) have been developed and appear to have adequate enzyme activity levels. Although there appears to be a relatively limited need for additional system development in this area, there is still a fundamental question as to whether any synergistic interplay exists between metabolic enzymes and transporters (i.e., does the presence of an efflux transporter influence the extent of metabolism ) and co-expression of CYP3A4 and transporters provides a pivotal experimental model. 

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Figure 5.6. A diagrammatic summary of adjusted hypoxia response systems (the AHRS) proposed as the ancestral physiological phenotype and as a phylogenetic adaptation to hypobaric hypoxia. Summary based largely upon studies of Quechuas and Sherpas. Essentially all of the characteristics summarized here are also expressed in individuals well adapted for endurance performance. In the latter, the main modification involves an upwards regulation of mitochondrial volume densities at the working tissues (altered expression of mitochondrial metabolic enzymes and metabolite transporters above), which is why this is referred to as a high-capacity version of the lower capacity high-altitude phenotype. See text for further details. (Modified from Hochachka et al., 1999.)...

Genetic polymorphisms of xenobiotic-metabolizing enzymes may result in expression of inactive enzymes or enzymes with a reduced or increased metabolic activity (Daly, 1995). For example, the incidence of hydralazine- and procainamide-induced lupus is higher or the disease starts earlier in individuals with the slow acetylator phenotype caused by mutant NAT-2 alleles than in individuals exhibiting the fast-acetylator phenotype (Woosley et al., 1978 von Schmiedeberg et al., 1999). 

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