Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver

Abstract

Drug-induced liver injury (DILI) is a global medical problem. The risk of DILI is often related to expression and activities of drugmetabolizing enzymes, especially cytochrome P450s (P450s). However, changes on expression and activities of P450s after DILI have not been determined. The aim of this study is to fill this knowledge gap. Acetaminophen (APAP) was used as a model drug to induce DILI in C57BL/6J mice at different ages of days 10 (infant), 22 (child), and 60 (adult). DILI was assessed by levels of alanine aminotransferase and aspartate aminotransferase in plasma with a confirmation by H&E staining on liver tissue sections. The expression of selected P450s at mRNA and protein levels was measured by real-time polymerase chain reaction and liquid chromatography-tandem mass spectrometry, respectively. The activities of these P450s were determined by the formation of metabolites from probe drugs for each P450 using ultraperformance liquid chromatography-quadrupole time of flight mass spectrometry. DILI was induced at mild to severe levels in a dose-dependent manner in 200, 300, and 400 mg/kg APAP-treated groups at child and adult ages, but not at the infant age. Significantly decreased expression at mRNA and protein levels as well as enzymatic activities of CYP2E1, 3A11, 1A2, and 2C29 were found at child and adult ages. Adult male mice were more susceptible to APAP-induced liver injury than female mice with more decreased expression of P450s. These results suggest that altered levels of P450s in livers severely injured by drugs may affect the therapeutic efficacy of drugs, which are metabolized by P450s, more particularly for males. SIGNIFICANCE STATEMENTThe current study in an animal model demonstrates that acetaminophen-induced liver injury results in decreased expression and enzyme activities of several examined drug-metabolizing cytochrome P450s (P450s). The extent of such decreases is correlated to the degree of liver injury severity. The generated data may be translated to human health for patients who have drug-induced liver injury with decreased capability to metabolize drugs by certain P450s.

Antituberculosis Drugs (Rifampicin and Isoniazid) Induce Liver Injury by Regulating NLRP3 Inflammasomes

“…Current studies have indicated that the pathogenesis of ATLI involves both hepatotoxicity and metabolic specificity [29]. Anti-TB drugs are initially transported to the liver, where they are transformed into metabolites via enzymatic reactions [30]. Subsequently, the metabolites, as immunogens, bind to endogenous proteins and subsequently cause liver immune damage or hepatotoxicity [31].…”

Alterations of Cytochrome P450–Mediated Drug Metabolism during Liver Repair and Regeneration after Acetaminophen-Induced Liver Injury in Mice

“…As a result, dose adjustment is needed to achieve optimized anesthesia time and avoid ADRs. A previous study observed immediate decreases of CYPs by AILI in a dosedependent manner in mice (Bao et al, 2020). However, how CYP-mediated drug metabolism is altered during recovery from AILI is not clear.…”

“…Plasma Levels of ALT and AST. Plasma levels of ALT and AST were measured as biomarkers of hepatocellular injury with a previously described method (Bao et al, 2020).…”

Vitamin C in orthopedic practices: Current concepts, novel ideas, and future perspectives

“…NSAIDs are used withcaution (or not recommended at all) in the immediate postoperative period on orthopaedic patients, due to the possible risk of bleeding 18 . Acetaminophen is preferred over NSAIDs or opioids due to its good safety profile, but high doses should be avoided in patients with underlying liver disorders 19,20 . High dose acetaminophen is often part of perioperative pain control regimens in combination with local nerve blocks, opioids or NSAIDS 21,22 …”

“…18 Acetaminophen is preferred over NSAIDs or opioids due to its good safety profile, but high doses should be avoided in patients with underlying liver disorders. 19,20 High dose acetaminophen is often part of perioperative pain control regimens in combination with local nerve blocks, opioids or NSAIDS. 21,22 Recently, there have been studies evaluating the role of vitamin C supplementation in the postoperative recovery and the prevention of CRPS.…”