Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen

Rongen, Anne van; Välitalo, Pyry A. J.; Peeters, Mariska Y. M.; Boerma, Djamila; Huisman, Fokko W.; Ramshorst, Bert van; Dongen, Eric P.A. van; Anker, Johannes N. van den; Knibbe, Catherijne A. J.

doi:10.1007/s40262-015-0357-0

Cited by 86 publications

(93 citation statements)

References 33 publications

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“…When obese individuals undergo weight-loss surgery, they exhibit a decrease in CYP2E1 activity concomitant with decreased body weight. The relationship between obesity and CYP2E1 may impact toxicology, as has been shown for the common drug acetaminophen in cultured cells treated with fatty acids 31 and in obese and non-obese humans 32 . In those cases, higher body fat and/or treatment of cells with free fatty acids resulted in higher CYP2E1 levels and higher production of the toxic quinoneimine metabolite N-acetyl-p-benzoquinone imine (NAPQI), resulting in more hepatotoxicity and mitochondrial dysfunction.…”

Section: Endogenous Role Of Cyp2e1mentioning

confidence: 98%

Toxicological implications of mitochondrial localization of CYP2E1

2017

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Cytochrome P450 2E1 (CYP2E1) metabolizes an extensive array of pollutants, drugs, and other small molecules, often resulting in bioactivation to reactive metabolites. Therefore, it is unsurprising that it has been the subject of decades of research publications and reviews. However, while CYP2E1 has historically been studied in the endoplasmic reticulum (erCYP2E1), active CYP2E1 is also present in mitochondria (mtCYP2E1). Relatively few studies have specifically focused on mtCYP2E1, but there is growing interest in this form of the enzyme as a driver in toxicological mechanisms given its activity and location. Many previous studies have linked total CYP2E1 to conditions that involve mitochondrial dysfunction (fasting, diabetes, non-alcoholic steatohepatitis, and obesity). Furthermore, a large number of reactive metabolites that are formed by CYP2E1 through metabolism of drugs and pollutants have been demonstrated to cause mitochondrial dysfunction. Finally, there appears to be significant inter-individual variability in targeting to the mitochondria, which could constitute a source of variability in individual response to exposures. This review discusses those outcomes, the biochemical properties and toxicological consequences of mtCYP2E1, and highlights important knowledge gaps and future directions. Overall, we feel that this exciting area of research is rich with new and important questions about the relationship between mtCYP2E1, mitochondrial dysfunction, and pathology.

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Section: Endogenous Role Of Cyp2e1mentioning

confidence: 98%

Toxicological implications of mitochondrial localization of CYP2E1

2017

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“…It results in increased fatty deposits in the liver parenchyma which is associated with altered drug metabolism. One of the proposed mechanisms for increased acetaminophen hepatotoxicity from obesity addresses the possibility of increased CYP2E1 activity in obese individuals . CYP2E1 is an isoenzyme responsible for converting acetaminophen to the toxic metabolite N ‐ acetyl ‐ p‐benzo ‐ quinoneimine .…”

Section: Introductionmentioning

confidence: 99%

Being overweight or obese as a risk factor for acute liver injury secondary to acute acetaminophen overdose

Chomchai

2017

Pharmacoepidemiology and Drug

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Purpose: Increased incidences of hepatotoxicity have been observed in obese patients with acute acetaminophen overdose. We evaluate whether the status of being overweight or obese is associated with increase in the development of hepatotoxicity and acute liver injury (ALI) in patients with acute acetaminophen overdose.Methods: This was a retrospective cohort study comparing the risk of hepatotoxicity and ALI between overweight or obese patients (body mass index [BMI] ≥ 25) and normal BMI patients (BMI ≤ 24.9) presenting with acute acetaminophen overdose at Siriraj Hospital during January 2004 to June 2012. All patients were treated with intravenous N-acetylcysteine. Psi parameters were calculated. High psi was defined as psi of ≥5.0 mM-hour. Data were analyzed using multinomial logistic regressions, odds ratio (OR), stratified OR, and 95% confidence interval (CI).Results: There were 197 patients who fulfilled the criteria for analysis, 35 (17.8%) were obese, 24 (12.2%) were overweight, and 138 (70%) were normal BMI cases. Hepatotoxicity and ALI developed in 25 (12.7%) and 40 (20.3%) cases, respectively. Multinomial logistic regression revealed that the overweight-obesity status and log 10 (psi value) were significant risk factors of ALI, with OR (95% CI) of 2.68 (1.21-5.95) and 1.74 (1.27-2.38), respectively, while only log 10 (psi) was a significant risk factor of hepatotoxicity with OR (95% CI) 378.51 (39.49-3627.99). From stratification, overweight-obesity had significant odds ratios for ALI in strata with low acetaminophen concentration, early initiation of N-acetylcysteine and low psi. Conclusion:We conclude that being overweight or obese is an independent risk factor of ALI in acute acetaminophen overdoses.

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“…Obesity has been considered as an inflammatory disease and liver function tests and inflammatory markers may be elevated in that cohort prior to surgery . Acetaminophen use and surgery are commonly associated with an increase in hepatic function tests but there is no evidence that these markers can be used as an early indicator of acetaminophen‐induced hepatotoxicity .…”

Section: Discussionmentioning

confidence: 99%

“…Acetaminophen use and surgery are commonly associated with an increase in hepatic function tests but there is no evidence that these markers can be used as an early indicator of acetaminophen‐induced hepatotoxicity . CYP2E1 activity may be increased in obese patients, but there is also commonly an increased glucuronide clearance and so less substrate is available for CYP2E1 metabolism. The impact of any increased CYP2E1 activity, duration of effect, production of NAPQI, and differences in glutathione production remain poorly quantified.…”

Section: Discussionmentioning

confidence: 99%

Acetaminophen pharmacokinetics in severely obese adolescents and young adults

Hakim

Anderson

Walia

et al. 2018

Pediatric Anesthesia

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Background Intravenous acetaminophen is commonly administered as an adjunctive to opioids during major surgical procedures, but neither the correct pharmacokinetic size descriptor nor the dose is certain in severely obese adolescents undergoing bariatric surgery. Methods Adolescents, 14‐20 years of age, with a body mass index (BMI) ≥95th percentile for age and sex or BMI ≥40 kg·m−2, presenting for laparoscopic or robotic assisted or vertical sleeve gastrectomy were administered intravenous acetaminophen (1000 mg) following completion of the surgical procedure. Venous blood was drawn for acetaminophen assay at eight time points, starting 15 minutes after completion of the infusion and up to 12 hours afterward. Time‐concentration data profiles were analyzed using nonlinear mixed effects models. Parameter estimates were scaled to a 70‐kg person using allometry. Normal fat mass was used to assess the impact of obesity on pharmacokinetic parameters. Results The study cohort comprised 11 female patients, age 17 SD 2 years with a weight of 125 SD 19 kg and a mean BMI of 46 SD 5 kg·m−2. The plasma acetaminophen serum concentration was 17 (SD 4) μg·mL−1 at 10‐20 minutes after completion of the infusion and 5 (SD 6) μg·mL−1 at 80‐100 minutes. A two‐compartment model, used to investigate pharmacokinetics, estimated clearance 10.6 (CV 72%) L·h·70 kg−1, intercompartment clearance 37.3 (CV 63%) L·h·70 kg−1, central volume of distribution 20.4 (CV 46%) L·70 kg−1, and peripheral volume of distribution 16.8 (CV 42%) L·70 kg−1. Clearance was best described using total body weight. Normal fat mass with a parameter that accounts for fat mass contribution (Ffat) of 0.88 best described volumes. Conclusion Current recommendations of acetaminophen to a maximum dose of 1000 mg resulted in serum concentrations below detection limits in all patients within 2 hours after administration. Dose is better predicted using total body mass with allometric scaling.

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Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen

Cited by 86 publications

References 33 publications

Toxicological implications of mitochondrial localization of CYP2E1

Toxicological implications of mitochondrial localization of CYP2E1

Being overweight or obese as a risk factor for acute liver injury secondary to acute acetaminophen overdose

Acetaminophen pharmacokinetics in severely obese adolescents and young adults

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