Screening for Drug-Drug Interactions with PXR and CYP3A4 Activation

Cytochrome P450 3A4 Enzyme

Numerous pharmaceutical companies have adopted assays for detecting activation of pregnane X receptor (PXR), a nuclear receptor known to regulate expression of cytochrome P450 (CYP450) drug-metabolizing enzymes (1). PXR is a transcription factor that has been designated the “master xenosensor” due to its ability to upregulate cellular levels of a variety of drug-metabolizing enzymes in response to drugs and foreign chemicals. Elevated levels of CYP450 enzymes can elicit alterations in the pharmacokinetics of co-administered drugs, which can result in adverse drug-drug interactions (DDI) or diminished bioavailability. By assessing PXR activation and CYP450 enzyme induction early in the drug development process, many companies hope to reduce late-stage clinical failures and minimize the high costs associated with bringing a new drug to market.

Proportion of drugs metabolized by different CYPs

A recent paper by Shukla et al. (2) examined over 2,800 clinically used drugs for their ability to activate human PXR (hPXR) and rat PXR (rPXR), induce human cytochrome P450 3A4 enzyme (CYP3A4) at the cellular level, and bind hPXR at the protein level. Several studies have identified PXR as playing a key role in regulating the expression of CYP3A4, an enzyme involved in the metabolism of more than 50% of all drugs prescribed in humans. Continue reading

Our Glorious Kitchen Garden

Having never grown a vegetable garden, I took advantage of some planting space in the Promega community garden in June 2010. Since most of my yard is shaded, this was the first time I had the opportunity to dig up soil, sow seeds, weed, water and harvest produce. I now have a greater appreciation for the effort it takes to place a ripe, beefsteak tomato on my plate. During this experience I learned that 1) I thankfully had two garden experts in my department, 2) not all winter squash is as edible as it appears on the seed package, 3) one gallon of water weighs 8.34 lbs. or 3.79 kgs, and 4) mosquitoes can form mushroom clouds when you disturb their shady garden retreats.

Looking toward the 2011 growing season, I was a bit skeptical when I heard that Promega’s Manager, Culinary Experience and new Head Chef, Nate Herndon, was overseeing the preparations of the employee community garden in addition to a new kitchen garden. Little did I know what culinary inspirations Nate and his staff would create for our three on-site cafeterias.  Continue reading

A Spider Homage

An Irregular Ode to a Spider

With black and yellow hazard signs you stretch en pointe to reach the next rung on a self-spun ladder and hold firm as each string vibrates upon my passing.

 A woven zipper brings the four corners under your command, drawing the unwilling to struggle along tightropes suspended unseen upon my passing.

 Dusted tangerine and black stockings expand to secure your body like a broach displayed on a wool coat in need of embellishment admired upon my passing. Continue reading

Insight into DICER1 Revealed in Macular Degeneration Research

A scene as it might be viewed by a person with macular degeneration.

I was sad to learn that a friend of mine was diagnosed with age-related macular degeneration (AMD) at the age of 62. Doctors told him that the blurriness he was experiencing in the center of his field of vision (see photo)  was a classic symptom of AMD. Millions suffer from this chronic condition that is now the leading cause of blindness in people 60 and older. This debilitating eye disease is caused by the degeneration of the macula, the central portion of the retina important for reading and color vision.
 
There were encouraging findings into the etiology of AMD in the March 11 issue of Nature by Kaneko et al., entitled “DICER1 Deficit Induces Alu RNA Toxicity in Age-Related Macular Degeneration”. The authors not only proposed a molecular mechanism leading to AMD, but also described a new function for the role of the microRNA processing-enzyme, DICER1. Continue reading

Tips for Multiplex Cell-Based Assay Success

The ability to analyze more than one cellular biomarker in a single sample is advantageous for a number of reasons. Multiplexing allows researchers to save money and time, while conserving precious samples. In addition, understanding the relationship between cell biomarkers can provide a more complete picture of cell health that can lead to improved predictive models for drug discovery. Understanding biomarker relationships can also minimize ambiguity in the data set and validate if a treatment effect is real or an artifact of the system. To avoid repeat experiments and extract the most biologically relevant data from multiplex assays, consider these tips when performing multiplex cell-based assays.
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An Interactive Wonderland: The British Library Web Site

Finding new topics that take you into deep discussions with strangers is always an interesting endeavor. I find that such conversations always include some mention of what people found helpful, entertaining or amazing on the internet. Recent conversations at an off-site training course I attended were no exception when the instructor shared one of her favorite web sites, the British Library. I am accustomed to having our local library web site offer helpful search functions to locate books, audio or video media on a topic that I am researching. However, I didn’t expect the amazing array of online capabilities that the British Library offered. This site went beyond my expectation of what a modern-day library experience could be.

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Ooooh, Fishy, Fish! Please Land on My Dish

Yes, I am a Monty Python fan and I like to play the “Find the Fish” video on YouTube when I need some midday amusement. However, this video brings up the topic of eating less red meat and enjoying more fish on my dish. My husband and I are trying to curb our beef-eating activities by diversifying the protein sources in our diet. We have recently adopted some dining rituals that include Friday Fish Fry (leaning more toward broiling, even though it’s hard to resist a traditional Wisconsin fish fry) and Meatless Mondays for vegetarian fare. One reason for doing this is to hopefully find more sustainable approaches to supporting a healthy diet.

So I was intrigued to learn more about fish farming (aquaculture) at sea when I read Sarah Simpson’s article in the February 2011 issue of Scientific American titled “The Blue Food Revolution”. Sustainability has become more important in many of the buying choices I have made lately, especially after learning that our global population will reach 7 billion in 2011 and is expected to grow to 9.3 billion by 2050. Yikes! How do we provide high-quality protein and nutrition to so many people? Continue reading

Pop Pi Quiz

Teachers, architects and engineers have found the mathematical constant, π, to be an invaluable tool for understanding and changing the world around us. Without Π, we would not be able to quickly calculate the area of a circle. To celebrate Pi Day (March 14th), today’s mental exercise will be to test your knowledge of Π. Are you ready for more Π?

1) What does Π represent?
a) The ratio of the circumference of a circle to its diameter
b) A rounded value of 3.14
c) The 16th letter in the Greek alphabet
d) All of the above Continue reading

Writing Your Worries Away

Experiencing sweaty palms, a rapid heart rate and nausea shouldn’t be the standard response before taking an important exam. However, for many students this has become a debilitating reaction when the pressure to perform academically affects their test scores.

I became more aware of this situation when my 13-year- old niece started “choking under pressure” on her math exams. She did well at solving problems in class. She completed her homework on time and received good scores. But when it came to the day of a math test, she would become anxious, her stomach would hurt and she failed to complete all the questions on the test. Consequently, her parents focused on personally sitting down to help her with homework assignments, assuming this would overcome her anxieties.

So it was just by chance that I picked up the January 14, 2011, issue of Science to read over lunch, when I came across the title “Writing About Testing Worries Boosts Performance in the Classroom”.  The title seemed counterintuitive though. Writing about fears makes them disappear? But as I’ll convey here, timing is everything. Continue reading

Red Remediation

On Monday, Oct. 4, 2010, a storage reservoir belonging to a Hungarian aluminum refinery, the Ajkai Timfoldgyar plant, burst releasing a 6–8ft wave of “red toxic sludge” with the volume of 35 million cubic feet roaring behind it. The sludge, enough to fill 440 Olympic swimming pools, killed nine people, injured more than 120 people, and contaminated plant and wildlife over a 16-square-mile area.

Hearing the term “red toxic sludge” conjured up images from those bad Toxic Avenger movies from the 1980s. I took a personal interest in this story because I have friends and family members living in Hungary, although not near the devastated towns of Kolontar and Devecser.

The red toxic sludge is a byproduct of the alumina extraction process. During aluminum (Al) production, alumina (Al2O3) is first extracted from bauxite under pressure using sodium hydroxide at 150-200°C (Bayer Process). Continue reading