MCAT Biological and Biochemical Foundations of Living Systems: Passage 7 — Flashcards

Use the following passage to answer questions:

Changes in the polyol pathway are a leading cause of diabetic complications. The substrate for the pathway is glucose, an essential monosaccharide that falls into the family known as aldoses because it contains a carbonyl group at the end of its carbon chain. In the first step of the pathway, an aldose reductase called ALR2, in the presence of cofactor NADPH, reduces glucose to sorbitol. Then sorbitol dehydrogenase converts sorbitol to fructose along with the reduction of NAD+. Under nondisease conditions, a low level of glucose enters the polyol pathway because ALR2 has a weak affinity for glucose; most glucose instead goes into the glycolytic pathway.

However, under conditions of hyperglycemia, the polyol pathway is activated, leading to the accumulation of sorbitol and a concomitant reduction in NADPH and NAD+. (The activity of sorbitol dehydrogenase does not increase to deal with the increased levels of sorbitol.) These changes occur primarily in tissues, including the lens, retina, kidney, and peripheral nerves, which do not depend on insulin to take up glucose. The increase in sorbitol, which is not easily cleared from cells, leads to cell swelling and changes in membrane permeability, primarily in the lens.

In addition, the drop in NADPH and NAD+ levels causes an increase in reactive oxygen species (ROS) and oxidative stress. Together, these changes, along with downstream enzymes that respond to changes in the polyol pathway and contribute to oxidative stress and inflammation, precipitate diabetic complications such as cataracts, retinopathy, neuropathy, and atherosclerosis. In the hope of combating some of these complications, researchers have developed a number of ALR inhibitors (ARIs) over the past several decades. Currently, epalrestat is the only ARI that has been approved for clinical use, and it is only approved in Japan, China, and Indi","The majority of ARIs have not been developed into useful therapies because of their low efficacy and adverse side-effect profiles, which is primarily due to their effects on ALRs that are not involved in the polyol pathway; for instance, ALR1 is active against toxic aldehydes. Consequently, researchers have been designing and testing new ARIs derived from a cyclical molecule called quinoxaline. To evaluate these derivatives' efficacy, the researchers have tested their ability to inhibit ALR2 based on their IC50 values. IC50 corresponds to the drug concentration that is required to inhibit 50% of the activity of an enzyme. However, it has been proposed that for a drug to effectively prevent and reduce diabetic complications, it may have to suppress oxidative stress as well as reduce ALR activity. As a result, researchers are working to develop drugs that also have anti-oxidative properties.

Compounds that exhibit both of these properties would be pursued for their ability to constitute important new multifunctional ARIs.