Hydroxychloroquine Causes DNA Damage in Mammalian Cells at Doses Used in People

By Megan Brooks

August 11, 2021

NEW YORK (Reuters Health) - Hydroxychloroquine (HCQ) causes DNA damage and mutations when added to cultured mammalian cells at concentrations comparable to those used in people, new research indicates.

"This drug is capable of inducing genetic mutation, which means we must carefully measure the risks and benefits of its use, especially in the context of clinical trials," lead investigator Ahmad Besaratinia, PhD, professor of research at the Department of Population and Public Health Sciences at the Keck School of Medicine at the University of Southern California (USC) said in a statement.

"Clearly, this drug has established benefits that outweigh the risk for patients with inflammatory diseases, malaria and other diseases," Dr. Besaratinia noted in a phone interview with Reuters Health.

"What was most concerning was the use of this drug for COVID-19, at least early in the pandemic, because we didn't have the data to really say that the benefits were greater than the risk," he noted.

It's since been conclusively demonstrated that HCQ is no better than placebo in COVID-19.

However, there are currently a large number of clinical studies that are using HCQ in healthy volunteers, "so it's important to know all of the potential health consequences to relay this information to participants in these trials," said Dr. Besaratinia. Genotoxicity is a "potential danger that they may face taking part in these studies, something that was not known at the time the clinical trials were initiated."

According to their report in DNA Repair, the researchers observed significant induction of DNA damage and mutagenic effects in primary mouse embryonic fibroblasts treated with therapeutic concentrations of HCQ.

The use of HCQ has long been associated with cardiotoxicity and ophthalmologic and gastrointestinal complications. Genotoxicity may be an additional side effect.

"The observed genotoxic effects of HCQ in vitro, achievable at clinically relevant doses, are novel and important, and may have significant implications for safety monitoring in patient populations," the study team writes.

"Surprisingly," Dr. Besaratinia told Reuters Health, "despite the decades-long use of this drug, the exact mechanism of action is only beginning to emerge and be understood, and the effects of this drug on the genome are completely under-studied."

The researchers caution against "over-interpreting or generalizing" their in vitro findings, as differences between mice and humans, as well as in vitro versus in vivo, may impact both the pharmacokinetics and pharmacodynamics of HCQ. The in vitro findings need to be validated in human cells and animal models, Dr. Besaratinia told Reuters Health.

SOURCE: https://bit.ly/37s4VDd DNA Repair, online July 16, 2021.