| Endocrine Disruption |
Actions : Disposal :: Metabolic Changes ::: CYP Activators In animals, several kinds of foreign molecules (xenobiotics) trigger cytochrome P450 (CYP) enzyme production, ultimately resulting in disposal of the invaders. Substances that activate or induce CYP include drugs; flavonoids (from fruits and vegetables); indole-3-carbinol (a cancer-preventing molecule in broccoli, cauliflower, kale, and Brussels sprouts); and chemicals such as alkylphenols (compounds in household and industrial detergents), phthalic acid, PCBs, and dioxin (Blumberg et al. 1998; Pascussi et al. 2003; Safe and Wormke 2003). CYP1, CYP2, and CYP3 are three main groups of CYP enzymes that can alter the xenobiotics so they can be quickly removed from the body (Pascussi et al. 2003). The process, though, is not always failsafe. Sometimes the enzymes convert foreign compounds into more dangerous cancer-causing substances or into endocrine disrupters that can interrupt hormone signaling or interfere with hormone production and break down. One example of this duplicity is CYP1A, a member of the CYP1 group, and its activating receptor, the aryl hydrocarbon receptor (AhR). AhR is an important nuclear receptor that binds to many synthetic and natural compounds, including dioxin, PCBs, polychlorinated dibenzodioxins, polychlorinated dibenzofurans, and indole-3-carbinol and other plant-derived chemicals (Safe and Wormke 2003). CYP1A is produced in cells and deactivates many hazardous foreign substances by hydroxylating (or adding OH groups to) chlorinated and brominated fat soluble compounds, most of which are industrial and combustion pollutants. Hydroxylation converts them into water soluble molecules that are easily excreted from the body. The AhR controls CYP1A production, turning it on or off as need arises. Once AhR binds to a foreign substance and is activated, it partners with a regulatory protein, moves to the nucleus, attaches to the promoter region of the CYP1A gene, and turns on production of CYP1A. This increases the amount of CYP1A available to degrade the noxious compounds that bound and initiated the receptor’s actions. But, the activated AhR can also turn on other enzymes that ultimately interfere with normal steroid and thyroid hormone signaling. For example, dioxin binding to AhR can inhibit the CYP enzyme that converts cholesterol into pregnenolone, the first step in making steroid hormones. Or it can turn on the liver and kidney enzymes responsible for breaking down thyroid hormone. In some cells, activation of AhR by dioxin or some PCBs blocks estrogen receptors from turning on gene expression (Safe and Wormke 2003). Natural steroids and xenobiotics interact with PXR in much the same way that steroids interact with their nuclear receptors. First, they bind and activate PXR, forming a complex with another nuclear receptor. The complex moves to the nucleus, attaches to a xenobiotic response element in the promoter region of the CYP3A gene, and turns on production of the CYP3A enzyme. Ironically, by binding to PXR and triggering CYP3A production, steroids and xenobiotics control their own destruction (Blumberg et al. 1998; Pascussi et al. 2003). In cell culture experiments, phthalic acid and nonylphenol interrupt this process by preventing the cell from degrading PXR, in essence jamming the disposal switch in the on position (Masuyama et al. 2002). This could be beneficial if the enzymes continue to break down the xenobiotics until they are gone, but it could also be harmful if too much steroid hormone is destroyed and blood hormone levels drop too low. The consequences of these opposite actions in living animals are not yet known. back to top References
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