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St. Jude researchers have discovered a chain of biochemical events that compromise the liver’s capacity to adequately clear many prescription drugs from the bodies of fetuses, young children and patients with liver cancer and other hepatic disorders.
“For the first time, we explain why the level of drug metabolizing enzymes is low, said Taosheng Chen, PhD, Chemical Biology and Therapeutics. “This finding is of both biological and clinical significance.” Chen is senior author of the study that appears in the November 7, 2008, issue of the Journal of Biological Chemistry.
Chen and his colleagues investigated how a specific protein in the nucleus of human liver cells—the human pregnane X receptor (hPXR)—regulates the expression of several critical drug metabolizing enzymes. One in particular, cytochrome P450 3A4 (CYP3A4), catalyzes the metabolism of more than 50 percent of clinically prescribed drugs.
“This is a significant pathway, and any changes in the expression level of this enzyme or the activity of hPXR will affect the efficacy of a drug and its toxicity,” Chen said.
In healthy adult livers, cells are not dividing and CYP3A4 is maintained at a level (which can be further elevated or reduced) that effectively metabolizes and clears drugs from the body, but when liver cells are dividing, the level of CYP3A4 drops precipitously—a phenomenon that has puzzled scientists. The new study explains why the level of the enzyme is significantly decreased in people during liver cell division.
The study also has implication in recent discoveries demonstrating that PXR expression and drug metabolism is not confined to the liver.
“The classical view is that drug metabolism primarily happens in the liver and that hPXR is primarily expressed in the liver,” Chen said. “Over the last several years, a number of reports have indicated that hPXR is also expressed in increasing number of extra-hepatic tissue.”
Among the potential implications of unraveling the hPXR pathway are: better understanding of the mechanisms of drug metabolism; highlighting the importance of and enabling the testing of many drugs under different physiological conditions, such as dividing versus non-dividing cells; developing tests that will predict the safe-dosage levels for drugs before they are tested on or given to pregnant women, children and cancer patients; and designing strategy to improve chemotherapy for some malignancies, including osteosarcoma, and liver, prostate and endometrial cancers.
The level of hPXR expression has been linked recently to the therapeutic efficacy of drugs used to treat these cancers in experimental models.
The new finding evolved from Chen’s interest in understanding the signal transduction pathways in normal and diseased cell systems. The scientists built their study on Chen’s earlier work at St. Jude and that of researchers at other institutions.
The liver has an amazing ability to regenerate itself, when necessary. “You can surgically remove up to two-thirds of the liver and within two weeks, the liver will grow back to its original size,” Chen said.
The liver begins developing during pregnancy and continues its maturation into early childhood. Because chemicals, other toxic materials and infections can damage the liver, the organ relies on healthy cells to regenerate and repair itself. Cancer cells remain in a state of uncontrolled replication.
In all these situations, liver cells are dividing, and the CYP3A4 level is much lower. “That poses a significant problem when patients take medicines,” Chen said. “When this enzyme is suppressed, you have toxicity problems because many drugs are not cleared out and build up in the body.”
Previous research had shown that hPXR regulates the expression of CYP3A4. Chen and his group sought to decipher how that happens in dividing liver cells. The investigators began with the hypothesis that hPXR activity is suppressed by signaling pathways activated in dividing liver cells and that chemical compounds might affect hPXR through affecting these signaling pathways. The scientists used high-throughput screening technology to investigate more than 6,000 chemical compounds, many of which were medications.
The screening process identified two tiny molecules, kenpaullone and roscovitine, which only weakly bind to hPXR but strongly activate its signaling pathway. Chen’s team found that in addition to this weak binding to hPXR, kenpaullone and roscovitine can inhibit a group of enzymes known as cyclin-dependent kinases (Cdks).
Inhibiting Cdks led to increased PXR-mediated expression of the CYP3A4 gene in dividing human liver cells—and a halt to cell division.
When the researchers reversed the pathway by activating the enzyme Cdk2, expression of the CYP3A4 gene decreased.
“Then we started to answer the question ‘What is the mechanism?’” Chen said.
What they discovered, and were the first to report, was that Cdk2 suppressed hPXR by adding a phosphate molecule to the protein, a process called phosphorylation.
Phosphorylating a protein can either increase or decrease its function. When PXR is phosphorylated by Cdk2, the activity of PXR is decreased, as is the level of CYP3A4 and the liver’s ability to metabolize many drugs.
“Understanding the molecular mechanisms of such signaling pathways holds enormous importance for designing effective therapies that prevent adverse drug reactions,” Chen said. “Our discovery that Cdk2 negatively regulates hPXR activity and CYP3A4 expression contributes to the understanding of such molecular mechanisms.”
Other authors of this paper include Wenwei Lin, PhD; Jing Wu; Hanqing Dong, PhD; David Bouck, PhD; and Fu-Yue Zeng, PhD; all of Chemical Biology and Therapeutics. The research was supported in part by ALSAC.