Effect of MRSA on CYP450: dynamic changes of cytokines, oxidative stress, and drug-metabolizing enzymes in mice infected with MRSA

Abstract

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) is a very damaging and widespread pathogen, which is associated with many diseases and causes serious infections. MRSA infection can modulate the effects of drugs, which may occur through an influence on cytochrome P450 (CYP450), the drug-metabolizing enzyme in the liver. In this study, we evaluated the underlying mechanism of drug failure or poisoning in MRSA infection.Materials and methodsMice were infected with three different doses of MRSA and the changes in CYP450 expression, cytokines, and oxidative stress markers were evaluated.ResultsThe administration of an attack dose of MRSA caused serious symptoms of infection and resulted in a 40% mortality rate in the mice. MRSA induced strong inflammation and oxidative stress in the mice, predominantly caused by significant increases in interleukin (IL)-1β, IL-4, IL-6, macrophage inflammatory protein, glutathione S-transferase (GST), and malondialdehyde, and decreases in oxygen radical absorbance capacity and glutathione levels in the liver. The expression of IL-2, tumor necrosis factor-α, and GST was briefly suppressed, but increased on days 3 and 7. The increased inflammation and oxidative stress further induced a significant decrease in the mRNA levels and activities of CYP450 1A2, 2D22, 2E1, and 3A1 in MRSA-infected mice within the first day of infection.ConclusionThese results show that MRSA infection leads to inflammation and oxidative stress, and reduces the expression levels and activities of drug metabolism enzymes, which decreased drug metabolism in patients infected with MRSA. Therefore, to avoid a drug overdose, the plasma concentration of patients with MRSA infection should be continuously monitored.

Distinct Effects of Escherichia coli,Pseudomonas aeruginosa and Staphylococcus aureus Cell Wall Component-Induced Inflammation on the Iron Metabolism of THP-1 Cells

“…The actions of these bacteria may depend on the structure of the bacterial cell wall components, which are recognized by different TLRs [ 44 , 45 ]. The MDR cell wall components activate distinct TLRs [ 46 , 47 ] that can result in the activation of additional signaling pathways, regulating not only cytokine production [ 43 , 48 ] but, for example, transcription factors that are involved in the regulation of iron metabolism as well, e.g., NRF2 that acts as a transcriptional regulator of both iron exporter ferroportin and the oxidative stress-induced protein heme oxygenase 1, which is also responsible for heme degradation [ 49 , 50 ]. Moreover, NRF2 can modify NFκB activity, which results in decreased cytokine production [ 50 , 51 , 52 , 53 ].…”

Tea tree oil inhibits hydrogen sulfide-induced oxidative damage in chicken lungs through CYP450s/ROS pathway

“…CYP450 is present in the tissues of most organisms and participates in the metabolism of H 2 S in vivo ( Tang et al, 2018 ). Previous studies have shown that acute H 2 S poisoning inhibited the activities of CYP2B6 (cytochrome P450 family 2 subfamily B member 6), CYP2D6 (cytochrome P450 family 2 subfamily D member 6), CYP1A2, and CYP2C9 (cytochrome P450 family 2 subfamily C member 9) enzymes in rats ( Wang et al, 2014 ).…”

Effects of infection of MRSA on the expression and activity of renal cytochrome P450s in mice

“…The expression of P450 enzyme was increased in the low and middle groups at day 7 after MRSA challenge. In addition, the mRNA expression and activity of Cyp2e1 were increased by MRSA at day 7, which was not observed in the liver enzymes of mice infected with MRSA (Tang et al, 2018). This is due to the fact that P450s in extrahepatic tissues can be regulated differentially by different inflammatory stimuli (Tindberg et al, 1996;Renton and Nicholson, 2000).…”