Ibuprofen at high doses linked to increased risk for liver injuries in new study

US: Ibuprofen, one of the most commonly used over-the-counter NSAIDs may cause very serious side effects than it was thought earlier, according to the researchers at the University of California. This study was published in the Scientific Reports.

Ibuprofen, an inhibitor of prostanoid biosynthesis, is a common pharmacological agent used for the management of pain, inflammation, and fever. However, its chronic usage at high doses is associated with increased risk for cardiovascular, renal, gastrointestinal and liver injuries. The underlying mechanisms of ibuprofen-mediated effects on the liver remain unclear.

Gomes, postdoctoral researcher Shuchita Tiwari, and colleagues had dosed aged-matched male and female C57BL/6J mice with a moderate amount of ibuprofen for a week -- equivalent to an adult human taking about 400 mg of the drug daily. Advanced mass spectrometry at UC Davis' Proteomics Core Facility was used to capture information on all the metabolic pathways in liver cells.

The researchers found that at least 34 different metabolic pathways were altered in male mice treated with ibuprofen. They include 

(1) energy metabolism,

(2) protein degradation,

(3) fatty acid metabolism and

(4) antioxidant system 

Independent validation of protein changes in energy metabolism and the antioxidant system was carried out by Western blotting and showed sex-related differences. Proteasome and immunoproteasome activity/expression assays showed ibuprofen induced gender-specific proteasome and immunoproteasome dysfunction in the liver.

The researchers also found that ibuprofen had different, and in some cases, opposite, effects in the livers of male and female mice eg., the proteasome -- a waste-disposal system that removes unwanted proteins -- responded differently in males and females. Ibuprofen elevated the activity of cytochrome P450, which breaks down drugs, in females but decreased it in males. The elevation in cytochrome P450 could mean that other drugs taken with ibuprofen could stay in the body for a longer duration in males and this has never been shown before.

Overall, the study indicated that moderate doses of ibuprofen can affect the liver more significantly than previously reported which includes a)proteasome dysfunction,

b)increased levels of H2O2,

c)impaired glycolytic pathways and

d)altered fatty acid synthesis and oxidation. 

For further reading click on the following link,

https://www.nature.com/articles/s41598-020-60053-y