Learning

Actions : Disposal :: Metabolic Changes ::: CYP Activators
  1. CYP1 and AhR
  2. CYP3 and PXR
  3. References

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.

CYP1 and AhR

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).




CYP3 and PXR
Another group of CYP enzymes, CYP3, is linked to a different chemical sensing receptor. The CYP3A enzyme hydroxylates approximately 60 percent of human drugs as well as natural steroid hormones like estradiol, testosterone, and progesterone. A nuclear receptor called PXR (pregnane-X-receptor ) switches on CYP3A production. PXR recognizes and binds a wide variety of compounds including natural steroids, drugs, flavonoids, and at least two endocrine disruptors, phthalic acid and nonylphenol (an alkylphenol detergent) (Masuyama et al. 2002; Pascussi et al. 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.





References
  • Blumberg, B, Sabbagh W, Juguilon H, Bolado J, van Meter C, Ong E, and Evans R. 1998. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12:3195-3205.
  • Masuyama H, Inoshita H, Hiramatsu Y, and Kudo T. 2002. Ligands have various potential effects on the degradation of pregnane X receptor by proteasome. Endocrinology 143:55-61.
  • Pascussi J, Gerbal-Chaloin S, Drocourt L, Maurel P, and Vilarem M. 2003. The expression of CYP2B6, CYP2C9, and CYP3A4 genes: A tangle of networks of nuclear and steroid receptors. Biochim Biophys Act 1619:243-253.
  • Safe S and Wormke M. 2003. Inhibitory aryl hydrocarbon receptor-estrogen receptor alpha cross-talk and mechanisms of action. Chem Res Toxicol 16:807-816.