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(A) Plasma alanine aminotransferase (ALT) and (B) aspartate aminotransferase (AST) activities over a time-course after the administration of APAP. On day 0, male Swiss Webster mice were treated with either STZ (200 mg/kg ip in citrate buffer, pH 4.3) or citrate buffer (10 ml/kg) alone. On day 10, both groups were treated with a single administration of APAP (600 mg/kg ip, in warm basic saline pH 8). Mice were euthanized at 0, 6, 12, 24, 36, 48, 72, and 120 h after APAP administration. For diabetic (DB) and nondiabetic (non-DB) mice treated with saline (vehicle for APAP) alone, samples were collected at 0, 12, and 72 h only (n 4 per group at all time points). Transaminase activities for 36, 48, 72, and 120 h time points are represented by only 30% surviving mice in the non-DB group. Results expressed as means SE. *Significantly different from non-DB control at the same time point. #Significantly different from the respective 0 h control. p 0.05.
Source publication
Streptozotocin (STZ)-induced diabetic (DB) mice challenged with single ordinarily lethal doses of acetaminophen (APAP), carbon tetrachloride (CCl4), or bromobenzene (BB) were resistant to all three hepatotoxicants. Mechanisms of protection against APAP hepatotoxicity were investigated. Plasma alanine aminotransferase, aspartate aminotransferase, an...
Contexts in source publication
Context 1
... ALT (Fig. 1A) and AST (Fig. 1B) in the non-DB mice exhibited significant increase of both transaminases, which correlated with the high lethality observed in this group. Note. On day 0, male Swiss Webster mice (27-33 g) were injected with either STZ (200 mg/kg, ip in citrate buffer, pH 4.3) or citrate buffer (10 ml/kg) alone. On day 10, both groups ...
Context 2
... ALT (Fig. 1A) and AST (Fig. 1B) in the non-DB mice exhibited significant increase of both transaminases, which correlated with the high lethality observed in this group. Note. On day 0, male Swiss Webster mice (27-33 g) were injected with either STZ (200 mg/kg, ip in citrate buffer, pH 4.3) or citrate buffer (10 ml/kg) alone. On day 10, both groups (STZ and vehicle ...
Citations
... The liver constitutes several damages related to oxidative stress according to dosage and duration of exposure [6]. In particular, repetitive and high toxic doses excess regenerative capacity and, unfortunately, develop hepatic injuries [7,8]. In the regeneration process, some growth factors, cytokines, and signaling have a potential role in hepatocyte growth, proliferation, and self-renewal. ...
... The hepatocytes select death under higher oxidative stress, such as higher acetaminophen administration, because they cannot resist or tolerate these catabolites. Thus, degeneration and necrosis are frequently observed due to such kinds of hepatotoxicities [7,34]. It is reported by Al-Doaiss [35] that hepatocytes of APAP-treated rats showed effects such as degeneration and necrosis. ...
Objectives
This study investigated the effect of krill oil (KO) on liver damage caused by acetaminophen (APAP).
Methods
In the present study, the control and APAP groups were given distilled water by gavage for 14 days. In addition, the KO and APAP+KO groups were given 500 mg/kg krill oil by gavage for 14 days. At the end of 14 days, 0.9 % sodium chloride solution (saline solution) administration was applied intraperitoneally to the control and KO groups. Meanwhile, 220 mg/kg acetaminophen was administered to the APAP and APAP+KO groups. While some biochemical parameters in plasma were examined, some oxidative stress parameters in plasma and liver tissue were evaluated. Apoptotic and inflammatory responses of some primer sequences determined by quantitative Real-Time PCR (qPCR) in liver tissue. After histopathological examination of liver tissue, immunohistochemical analysis was performed with Wnt inhibitory factor-1 (Wif-1), beta-catenin (β-Catenin), and 8-hydroxy-2′-deoxyguanosine (8-OHdG).
Results
The Wif-1 positivity in hepatocytes increased significantly in the APAP group (5.29 ± 0.71) compared to the control (1.14 ± 0.51), and KO (2.14 ± 0.55) groups (p<0.001). The 8-OHdG positivity in hepatocytes increased significantly in the APAP group (19.57 ± 0.58) compared to the control (0.43 ± 0.20), KO (3.57 ± 0.48), and APAP+KO (4.00 ± 2.53) groups (p<0.001).
Conclusions
As a result, krill oil could be used as a nutritional supplement to protect the liver against acetaminophen-induced liver injury.
... Contrasting with the study by Wang et al. [184], several investigations in streptozotocintreated rodents showed that T1DM protected against APAP-induced acute hepatotoxicity [189][190][191]. The exact reasons for these discrepancies are unknown although higher APAP glucuronidation and improved liver repair in diabetic animals might play a role [189][190][191]. ...
... Contrasting with the study by Wang et al. [184], several investigations in streptozotocintreated rodents showed that T1DM protected against APAP-induced acute hepatotoxicity [189][190][191]. The exact reasons for these discrepancies are unknown although higher APAP glucuronidation and improved liver repair in diabetic animals might play a role [189][190][191]. However, it is worth mentioning that hepatic CYP2E1 activity was not increased in these studies, thus contrasting with many other investigations reporting CYP2E1 induction in streptozotocin-treated rodents [10,167,[185][186][187][188]. ...
The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity.
... We used the resulting model to simulate the effect of different blood concentrations of APAP on the intracellular metabolism and DDR pathway activation in human hepatocytes. From studies that monitored APAP blood plasma concentrations in humans and mice, we deducted that the ratio between the administered dose (oral for human and intraperitoneal for mice, in mg/kg) and the plasma concentration within the first 15-30 min after exposure (in µg/ml) is~1 (Supplementary Table 1) 19,25,[71][72][73][74][75] . Therefore, we chose a range of initial APAP values between 250 for low and 650 for high levels of adversity that match realistic levels of APAP in the blood plasma 76 and that correspond to similar administration quantities (albeit expressed in mg/kg). ...
... Mice do not all die or all stay alive after exposure to equal amounts of APAP that results in a similar extent of necrosis 25 , demonstrating the complexity of this relation. Existing models to predict mortality make use of damage biomarkers in plasma 61,123 , but other factors such as the extent of senescence 14,124 , potential of regeneration 74 and effectivity of the immune response 125 also contribute to the interindividual difference in susceptibility to liver failure and death. Therefore, accurate mortality predictions are not straightforward and misclassification by models is common. ...
In high dosages, acetaminophen (APAP) can cause severe liver damage, but susceptibility to liver failure varies across individuals and is influenced by factors such as health status. Because APAP-induced liver injury and recovery is regulated by an intricate system of intra- and extracellular molecular signaling, we here aim to quantify the importance of specific modules in determining the outcome after an APAP insult and of potential targets for therapies that mitigate adversity. For this purpose, we integrated hepatocellular acetaminophen metabolism, DNA damage response induction and cell fate into a multiscale mechanistic liver lobule model which involves various cell types, such as hepatocytes, residential Kupffer cells and macrophages. Our model simulations show that zonal differences in metabolism and detoxification efficiency are essential determinants of necrotic damage. Moreover, the extent of senescence, which is regulated by intracellular processes and triggered by extracellular signaling, influences the potential to recover. In silico therapies at early and late time points after APAP insult indicated that prevention of necrotic damage is most beneficial for recovery, whereas interference with regulation of senescence promotes regeneration in a less pronounced way.
... DM is also associated with liver diseases such as non-alcoholic fatty liver disease [26] and diabetic hepatosclerosis [27], causing abnormal hepatic function, which may affect drug biotransformation. The impact of diabetes on drug biotransformation has been observed in animal models [28,29]. Watkins et al. [28] demonstrated in their study that biliary excretion of acetaminophen decreased by 65%, with a 280% increase in urinary excretion, resulting in unaltered total clearance. ...
Diabetic patients have an increased propensity to Candida sp. infections due to disease-related immunosuppression and various other physiological alterations. The incidence of candidiasis has increased in number over the years and is linked to significant morbidity and mortality in critically ill and immunosuppressed patients. Treatment of infection in diabetic patients may be complicated due to the various disease-related changes to the pharmacokinetics and pharmacodynamics (PK/PD) of a drug, including antifungal agents. Application of PK/PD principles may be a sensible option to optimise antifungal dosing regimens in this group of patients. Further studies on PK/PD of antifungals in patients with diabetes mellitus are needed as current data is limited or unavailable.
... Importantly, the extent of hyperglycemia and ketosis after STZ treatment depends on numerous factors including species and strains, gender, diet, time of injection in the day and time period after last administration [21,[40][41][42]. These variations might explain that in a few studies, higher hepatic CYP2E1 expression was not detected in STZ-treated rodents and that T1D diabetes protected against APAP-induced liver injury [43,44]. In these studies, reduced APAP hepatotoxicity resulted from increased APAP detoxification into its non-toxic glucuronide conjugate and higher urine elimination secondary to polyuria [43,44]. ...
... These variations might explain that in a few studies, higher hepatic CYP2E1 expression was not detected in STZ-treated rodents and that T1D diabetes protected against APAP-induced liver injury [43,44]. In these studies, reduced APAP hepatotoxicity resulted from increased APAP detoxification into its non-toxic glucuronide conjugate and higher urine elimination secondary to polyuria [43,44]. Of note, STZ-induced T1D was shown to favour hepatotoxicity of thioacetamide [45] and carbon tetrachloride [26], two toxins also generating highly reactive and toxic metabolites via CYP2E1. ...
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.
... There have been many studies reporting the relationships between diabetic states and DILI. For APAP-induced hepatotoxicity, it has been reported that hepatotoxicity is increased in type 1 diabetic rats but is decreased in type 1 or 2 diabetic mice when compared to healthy animals (Price and Jollow, 1982;Sawant et al., 2006;Watkins and Sherman, 1992;Jeffery et al., 1991;Shankar et al., 2003aShankar et al., , 2003b. Taken together, our results indicate that a diabetic state is one of the risk factors for APAP-induced hepatotoxicity. ...
Some patients encounter hepatotoxicity after repeated acetaminophen (APAP) dosing even at therapeutic doses. In the present study, we focused on the diabetic state as one of the suggested risk factors of drug-induced liver injury in humans and investigated the contribution of accelerated gluconeogenesis to the susceptibility to APAP-induced hepatotoxicity using an animal model of type 2 diabetes patients. Sprague-Dawley (SD) rats and spontaneously diabetic torii (SDT) rats were each given APAP at 0 mg/kg, 300 and 500 mg/kg for 35 days by oral gavage. Plasma and urinary glutathione-related metabolites, liver function parameters, and hepatic glutathione levels were compared between the non-APAP-treated SDT and SD rats and between the APAP-treated SDT and SD rats. Hepatic function parameters were not increased at either dose level in the APAP-treated SD rats, but were increased at both dose levels in the APAP-treated SDT rats. Increases in hepatic glutathione levels attributable to the treatment of APAP were noted only in the APAP-treated SD rats. There were differences in the profiles of plasma and urinary glutathione-related metabolites between the non-APAP-treated SD and SDT rats and the plasma/urinary endogenous metabolite profile after treatment with APAP in the SDT rats indicated that hepatic glutathione synthesis was decreased due to accelerated gluconeogenesis. In conclusion, SDT rats were more sensitive to APAP-induced chronic hepatotoxicity than SD rats and the high susceptibility of SDT rats was considered to be attributable to lowered hepatic glutathione levels induced by accelerated gluconeogenesis.
... Furthermore, mice with streptozotocin-induced diabetes were resistant to APAP-induced injury because of a higher regeneration capacity, and the inhibition of regeneration by an antimitotic agent (colchicine) in these mice resulted in increased mortality. 28 Finally, accumulating clinical evidence supports the association of liver regeneration after APAP overdose with enhanced survival. For instance, higher b-catenin activation was correlated with higher spontaneous liver regeneration, preventing the need for liver transplantation, 13 and increased serum a-fetoprotein, a marker of hepatocyte proliferation, was correlated with survival in patients with APAP-induced ALF. 14 Together, these data indicate that stimulating liver regeneration in APAP-induced ALF patients can potentially improve survival and recovery. ...
Acetaminophen (N-acetyl-para-aminophenol; APAP) overdose is the most common cause of acute liver failure in the Western world, with limited treatment opportunities. For years, research on APAP overdose has been focused on investigating the mechanisms of hepatotoxicity, with limited success in advancing therapeutic strategies. Acute liver injury after any insult, including APAP overdose, is followed by compensatory liver regeneration, which promotes recovery and is a crucial determinant of the final outcome. Liver regeneration after APAP-induced liver injury is dose dependent and impaired after severe APAP overdose. Although robust regenerative response is associated with spontaneous recovery and survival, impaired regeneration results in faster progression of injury and death after APAP overdose. APAP hepatotoxicity–induced liver regeneration involves a complex time- and dose-dependent interplay of several signaling mediators, including growth factors, cytokines, angiogenic factors, and other mitogenic pathways. Compared with the liver injury, which is established before most patients seek medical attention and has proved difficult to manipulate, liver regeneration can be potentially modulated even in late-stage APAP-induced acute liver failure. Despite recent efforts to study the mechanisms of liver regeneration after APAP-induced liver injury, more comprehensive research in this area is required, especially regarding factors that contribute to impaired regenerative response, to develop novel regenerative therapies for APAP-induced acute liver failure.
... One of the ways in which paracetamol causes tissue injury is by depletion of cytosolic and mitochondrial glutathione, which leads to the loss of cellular homeostasis [16]. This may further result in a reduced ATP content that will hamper a lot of biochemical events. ...
... All buffers were prepared in double-glass distilled water. 16 albino rats of the Wistar strain weighing 80-100 g were purchased from the animal house of the Department of Physiology, College of Health Sciences, University of Port Harcourt. The animals were kept in a separate animal room, on a 12 h light/dark cycle, at a room temperature of 22 ± 2°C and with free access to food and water ad libitum. ...
... The results reveal that paracetamol caused both liver and kidney damage at high concentrations which can be linked to lipid peroxidation [Tables 1-3]. One of the ways by which paracetamol causes tissue injury is by depletion of cytosolic and mitochondrial glutathione which leads to the loss of cellular homeostasis [16]. This may further result in reduced ATP content that will hamper a lot of biochemical events. ...
... In addition to H 2 O 2 and peroxinitrite, NAPQI is also produced in the ER and is known to play a central role in APAP-induced hepatotoxicity. 2,3,47 In the ER and cytoplasm, changes were seen in both protein abundance and oxidative modifications. In general, their abundance was decreased and they were heavily S-nitrosylated and/or S-sulfenylated. ...
Acetaminophen (APAP) is possibly the most widely used medication globally and yet little is known of its molecular effects at therapeutic doses. Using a novel approach, we have analysed the redox proteome of hepatocytes treated with APAP and quantitated both individual protein abundance and their reversible S-nitrosylation (SNO) and S-sulfenylation (SOH) modifications by mass spectrometry. APAP treatment results in a late, transient increase in ATP production and a multiplicity of alterations in protein abundance and modification. The majority of the differentially SNO or SOH modified proteins are found in the endoplasmic reticulum and cytosol suggesting that the source of reactive species is there. Functions of the mitochondrial and nuclear proteins affected suggest that their modifications are compensatory. The cellular response indicates: constraint of fatty acid metabolism; reduction in ribosome construction and protein synthesis (to conserve ATP); maintenance of glutathione levels (by increased synthetic capacity) and an increased NADPH production (via the pentose phosphate pathway). This response appears to be coordinated, directly or indirectly, by the canonical Wnt and Nrf2 paracrine signalling pathways. Combined with the known role of NAPQI, these studies suggest that the physiological and toxicological hepatocyte responses form a continuum: therapeutic doses of APAP produce reactive species and NAPQI in the cytoplasm but result in little permanent damage. The cell mounts a multifaceted response which minimises disruption and repairs are effected within a day or two. Higher doses of APAP lead to intensified reactive species production which increasingly disturb mitochondrial function and eventually lead to cellular necrosis.
