Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients

Abstract

Drug-induced Liver Injury (DILI) is becoming a significant public health issue because of its potential impact, not only on patients but also on the development of new drugs. DILI events are also the main cause of regulatory action pertaining to drugs, including denial of marketing approval, restrictions with respect to clinical indications and withdrawal from the marketplace (Lee, 2003;Smith and Schmid, 2006). Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent for relief of mild and moderate pain and is available as an over-the-counter medication. Overdoses of APAP, however, cause severe acute hepatotoxicity both in animals (Lauterburg et al., 1983) and humans (Black, 1984;Davidson and Eastham, 1966;Thomson and Prescott, 1966;Schiødt et al., 1997). APAP at therapeutic doses is rapidly metabolized in the liver principally through glucuronidation and sulfation, and only a small portion is oxidized by cytochrome P-450 2E1 to generate a highly reactive and cytotoxic intermediate, N-acetyl-p-benzoquinoneimine (NAPQI), which is quickly conjugated by hepatic glutathione to yield a harmless water-soluble product, mercapturic acid (Lee et ABSTRACT -Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent. However, some patients encounter hepatotoxicity after repeated APAP dosing at therapeutic doses. In the present study, we focused on the nutritional state as one of the risk factors of APAP-induced chronic hepatotoxicity in humans and investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model mimicking undernourished patients. Rats were divided into 2 groups: the ad libitum fed (ALF) and the restricted fed (RF) rats and were assigned to 3 groups (n = 8/group) for each feeding condition. The animals were given APAP at 0, 300 and 500 mg/kg for 99 days under each feeding condition. Plasma and urinary glutathione-related metabolites and liver function parameters were measured during the dosing period and hepatic glutathione levels were measured at the end of the dosing period. In the APAP-treated ALF rats hepatic glutathione levels were increased and hepatic function parameters were not changed, but in the APAP-treated RF rats hepatic glutathione levels were decreased at 500 mg/kg and hepatic function parameters were increased at 300 and 500 mg/kg. Moreover the urinary endogenous metabolite profile after long-term treatment with APAP in the ALF and RF rats was similar to that in human non-responders and responders to APAP-induced chronic hepatotoxicity, respectively. In conclusion, the RF rats were more sensitive to APAP-induced chronic hepatotoxicity than the ALF rats and were considered to be a useful model to estimate the contribution of the nutritional state of patients to APAP-induced chronic hepatotoxicity.

N‐Acetyl cysteine does not prevent liver toxicity from chronic low‐dose plus subacute high‐dose paracetamol exposure in young or old mice

“…Although this did not achieve statistical significance, it does suggest that the paracetamol diet may have caused some low-level damage in some mice which is not measurable in the circulation, at least not after 6 weeks of treatment. Previous animal studies that have dosed once daily, via intraperitoneal injection or oral gavage, for 30-99 days with 75-300 mg/ kg showed no evidence of toxicity as assessed by liver function tests [7][8][9]. Our study, which modelled a more clinically relevant exposure to paracetamol at regular intervals over a full day, as it was consumed in the diet, rather than once daily, appears to confirm these findings.…”

“…There have been few animal studies of chronic paracetamol exposure. Two rat studies, and one mouse study, showed that low-dose paracetamol administered daily did not cause liver toxicity in the absence of other risk factors [7][8][9]. Several rat and BALB/c mouse studies have found that pretreatment with nontoxic doses of paracetamol for 4-8 days before exposure to a high dose of paracetamol can protect against hepatotoxicity, through mechanisms including reduction in cytochrome (CYP)2E1 activity, and increased glutathione (GSH) levels [10][11][12].…”

Liver Autophagy in Anorexia Nervosa and Acute Liver Injury

“…Chronic exposure to alcohol decreases autophagic flux by inhibiting the fusion of autophagosomes with lysosomes [87]. This may explain why chronic consumption to alcohol favors APAP hepatotoxicity [88, 89]. Besides induction of autophagy, APAP also induces the formation of mitochondrial spheroids in vivo [90], which are ring-like spherical structures with lumen surrounded by mitochondrial membranes that can contain cytoplasmic material.…”

Paracetamol to induce ductus arteriosus closure: is it valid?

“…It is reasonable to anticipate population specific toxicity because the activity of CYP2E1—the major enzyme producing NAPQI—is not yet quantified, while data on the NAPQI detoxification capacity through glutathione conjugation in neonates are also lacking 27 28. Furthermore, immaturity of hepatic transporters or individual patient characteristics like malnutrition may further contribute to specific vulnerability 29 30…”