Environmental factors and pharmacological response
The regulation of the expression of CYP3A4 provides an illuminating example of how environmental factors exert significant influences on this and other enzymes that contribute significantly to drug metabolism. CYP3A4 is responsible for the metabolism of many antidepressants, benzodiazepines, antibiotics, immunosuppressants, and antiviral agents.13,14 It has long been known that the gene encoding the enzyme is highly responsive to environmental influences that can lead to drug-drug, nutrient-drug, and medicinal herb–drug interactions.
Grapefruit juice and red wines have long been known to inhibit the activity of the enzyme, which can lead to potentially lethal toxicity with immunosuppressants and antivirals and to oversedation with benzodiazepines and nefazodone(Drug information on nefazodone).
On the other hand, St John’s wort dramatically induces the production of CYP3A4, which causes drugs to break down at a faster rate and dramatically reduces their concentration in the blood and the brain. The result may be reduced effectiveness and symptomatic relapse. The mechanism for such induction involves the steroid and xenobiotics receptor (SXR) involved in the regulation of the metabolism of steroids and phytochemicals. The SXR binds to the promoter region of the CYP3A4 gene and regulates its transcription. As the name implies, the SXR is activated by a wide range of foreign substances, including manufactured drugs, medicinal herbs, nutrients, and environmental toxins. In addition to CYP3A4, the SXR regulates a number of other drug-metaboliz-ing enzymes and membrane protein transporters, and it serves as the master key for speeding up metabolism when the organism is ex-posed to potentially harmful foreign substances.20
Dietary practices and the use of medicinal herbs vary widely across cultural groups, which represents another major reason for variations in drug responses across ethnic and cultural populations. For example, the metabolism of drugs such as antipyrine and clomipramine(Drug information on clomipramine) is significantly slower in Sudanese people and South Indians while they reside in their native countries; however, when they immigrate to Western countries and gradually adapt to the diet of the host society, their metabolism of these drugs speeds up and reaches levels found in white populations.20,21 Similar mechanisms may be responsible for observed differences in the metabolism of alprazolam(Drug information on alprazolam), adinazolam, and clomipramine across populations. East Asians and Asian Americans metabolize these agents more slowly than do their white counterparts, probably a result of environmental rather than genetic factors.22-24
Dietary differences and the use of medicinal herbs also vary significantly in different regions of the world and across different ethnic and cultural groups. Many medicinal herbs are potent inhibitors or inducers of CYP enzymes, which may also contribute to observed cross-ethnic and cross-cultural variations in drug metabolism.25