Does genetics determine whether drugs help or harm?

We are all aware of the risks of high cholesterol for cardiovascular health, but it is also a lipid that we cannot live without.. Our bodies need cholesterol to form cell membranes, steroid hormones, and vitamin D. And the brain contains about 20-25% of the body’s cholesterol, which it needs to grow and function. So what happens when cholesterol synthesis in our brain is disrupted?

Karoly Mirnics, a professor at the University of Nebraska Medical Center, and his lab have long studied the molecular basis of brain disorders. Their recent post on psychotropic drugs that inhibit cholesterol biosynthesis in the brain was published in the Lipid Research Journal.


“Cholesterol is synthesized by a complex, multi-branch cascade of events, but there is one particular molecule that is the direct precursor of cholesterol called 7-dehydrocholesterol or 7-DHC,” Mirnics said. “7-DHC is very unstable, breaks down very quickly, and is the most oxidizable lipid known to mankind.”

An enzyme converts 7-DHC to cholesterol in the last step of cholesterol biosynthetic pathway. In humans, the DHCR7 gene provides instructions to produce this enzyme, and mutations in this gene can cause Smith-Lemli-Opitz syndrome, or SLOS. Symptoms of this rare disease, including growth and developmental delays, appear before or shortly after birth. Elevated 7-DHC is a common molecular marker for the diagnosis of SLOS.

“About 10 years ago, several adult patients on commonly used psychotropic medications were misdiagnosed with SLOS due to their elevated 7-DHC levels,” Mirnics said. “These patients didn’t have a mutation in the gene (DHCR7), so we asked if it could be from the drugs, and that started our search.”

Aripiprazole, or ARI, an antipsychotic used to treat schizophrenia and bipolar disorder, and trazodone, or TRZ, an antidepressant, are commonly prescribed in the United States. Psychiatrists often treat patients with multiple drugs simultaneously, but the side effects of these drugs are not fully known. Mirnics and his group therefore set out to study how they affect the molecular and biochemical functions of the brain.

“I should point out that our studies are all in mouse models, but the cholesterol biosynthetic pathway in mice is conserved in vertebrates, including humans,” Mirnics said.

When the researchers treated cell cultures and genetically modified mice with ARI and TRZ, they found that the combination therapy disrupted cholesterol biosynthesis in developing brain cells such as neurons and astrocytes. Adult mice treated with ARI and TRZ had elevated levels of 7-DHC – as did patients who were misdiagnosed with SLOS.

SLOS is very rare. Babies with the disease must inherit two non-functional or mutated copies of the DHCR7 gene from each parent. Many more people, around 1% to 3% of the population, are asymptomatic carriers with one mutated copy and one functional copy of the gene. Mirnics warns that people with genetic mutations in the cholesterol biosynthetic pathway are most vulnerable to treatment with drugs like ARI and TRZ.

“I’m not saying these drugs are bad,” Mirnics said. “But they may not be the best choice for people with a genetic predisposition, or during pregnancy without knowing the genotype of the parents or the baby.”

The laboratory attempts to list all commonly used drugs that interfere with cholesterol biosynthesis. Mirnics expects this information to be useful to physicians, particularly when prescribing drugs to patients with genetic predispositions. In the near future, personalized medicine will exist in which our genetics could determine our drugs.

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