Cytochrome P450 regulation and drug biotransformation during inflammation and infection.

The expression of cytochrome P450 and related biotransformation is altered during the operation of host defense mechanisms. This has major implications in inflammation and infection when the capacity of the liver and other organs to handle drugs is severely compromised. In most cases individual cytochrome P450 forms are down regulated at the level of gene transcription with a resulting decrease in the corresponding mRNA, protein and enzyme activity. The loss in drug metabolism is channeled predominantly through the production of cytokines which ultimately modify specific transcription factors. Other proposed mechanisms that apply to specific cytochrome P450s involve post translational steps including enzyme modification and increased degradation. When inflammatory responses are confined to the brain there is a loss of cytochrome P450 not only in the brain but also in peripheral tissues. This involves a yet to be identified mode of signaling between the brain and periphery but it does involve the production of cytokines from a peripheral source. In clinical medicine there are numerous examples of a decreased capacity to handle drugs during infections and disease states that involve an inflammatory component. This often results in altered drug responses and increased toxicities. Inflammation mediated alterations in the metabolism of endogenous compounds can lead to altered physiology. Changes in drug handling capacity during inflammation/infection will continue to be one of the many factors that complicate therapeutics.