Research Article Details
| Article ID: | A43098 |
| PMID: | 32571750 |
| Source: | Clin Res Hepatol Gastroenterol |
| Title: | Cytochrome P450 2E1 should not be neglected for acetaminophen-induced liver injury in metabolic diseases with altered insulin levels or glucose homeostasis. |
| Abstract: | Acetaminophen (APAP) hepatotoxicity is mediated by N-acetyl-p-benzoquinone imine (NAPQI), a highly toxic metabolite generated by cytochrome P450 2E1 (CYP2E1). Thus, pathological conditions increasing CYP2E1 activity can favour APAP-induced liver injury, which is characterized by massive hepatocellular necrosis and secondary sterile inflammation. In a recent work, Wang et al. showed that APAP-induced hepatotoxicity was exacerbated in a murine model of type 1 diabetes induced by the administration of streptozotocin (STZ). Higher hepatotoxicity was in particular associated with a stronger proinflammatory response of the resident macrophages. Although the authors carried out numerous investigations, they did not study hepatic CYP2E1, nor discussed the possible role of this enzyme in the exacerbation of APAP hepatotoxicity. However, numerous investigations reported hepatic CYP2E1 induction in STZ-treated rodents, which could be secondary to insulinopenia and ketosis. This commentary also discusses the role of insulin resistance in CYP2E1 induction observed in obesity and nonalcoholic fatty liver disease. Investigators studying APAP-induced liver injury in the context of insulinopenia or hyperinsulinemia are thus encouraged to consider CYP2E1 as a significant player in the observed phenotypic changes. |
| DOI: | 10.1016/j.clinre.2020.05.018 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D002 | Acetaminophen | Chemical drug | DB00316 | PTGES3 inhibitor; TRPV1 activator | Antipyretic drug; non-narcotic analgesic | Under clinical trials | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |