Nonalcoholic Fatty Liver Disease (NAFLD) and Hepatic Cytochrome P450 (CYP) Enzymes

Jamwal, Rohitash; Barlock, Benjamin J.

doi:10.3390/ph13090222

Cited by 37 publications

(28 citation statements)

References 106 publications

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“…The effect of NAFLD/lipid accumulation in CYP450s has been studied to assess the disease-associated impact on drug metabolism and to provide recommendations for at-risk populations including postmenopausal women [ 42 ]. To date, little is known about how lipid accumulation and sex hormone deficiency after ovariectomy influence CYPs.…”

Section: Discussionmentioning

confidence: 99%

Ovariectomy-Induced Hepatic Lipid and Cytochrome P450 Dysmetabolism Precedes Serum Dyslipidemia

Malínská

Hüttl

Miklánková

et al. 2021

IJMS

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Ovarian hormone deficiency leads to increased body weight, visceral adiposity, fatty liver and disorders associated with menopausal metabolic syndrome. To better understand the underlying mechanisms of these disorders in their early phases of development, we investigated the effect of ovariectomy on lipid and glucose metabolism. Compared to sham-operated controls, ovariectomized Wistar female rats markedly increased whole body and visceral adipose tissue weight (p ˂ 0.05) and exhibited insulin resistance in peripheral tissues. Severe hepatic triglyceride accumulation (p ˂ 0.001) after ovariectomy preceded changes in both serum lipids and glucose intolerance, reflecting alterations in some CYP proteins. Increased CYP2E1 (p ˂ 0.05) and decreased CYP4A (p ˂ 0.001) after ovariectomy reduced fatty acid oxidation and induced hepatic steatosis. Decreased triglyceride metabolism and secretion from the liver contributed to hepatic triglyceride accumulation in response to ovariectomy. In addition, interscapular brown adipose tissue of ovariectomized rats exhibited decreased fatty acid oxidation (p ˂ 0.01), lipogenesis (p ˂ 0.05) and lipolysis (p ˂ 0.05) despite an increase in tissue weight. The results provide evidence that impaired hepatic triglycerides and dysregulation of some CYP450 proteins may have been involved in the development of hepatic steatosis. The low metabolic activity of brown adipose tissue may have contributed to visceral adiposity as well as triglyceride accumulation during the postmenopausal period.

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Section: Discussionmentioning

confidence: 99%

Ovariectomy-Induced Hepatic Lipid and Cytochrome P450 Dysmetabolism Precedes Serum Dyslipidemia

Malínská

Hüttl

Miklánková

et al. 2021

IJMS

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“…Another metabolic feature of MAFLD and obesity is the altered hepatic expression and activity of numerous xenobiotic metabolizing enzymes (XMEs), extensively discussed in several previous reviews [30][31][32][33][34]. XME activity is also altered in the intestine and kidneys of obese individuals, further impacting drug pharmacokinetics [33].…”

Section: Mafld and Changes In Xenobiotic Metabolismmentioning

confidence: 99%

“…In addition to metabolism, the alteration in drug absorption, distribution and elimination is observed in obesity due to altered gastric emptying and gut permeability, higher cardiac output and increased volume of distribution and glomerular filtration [33,35,36]. Although the impact of obesity and associated diseases (e.g., MAFLD and diabetes) on drug pharmacokinetics have been explored in many studies [32][33][34][35]37], much less is known regarding other xenobiotics such as industrial chemicals. Nevertheless, it is conceivable that several molecules present altered pharmacokinetics in obese people, which might change their toxicological profile.…”

Section: Mafld and Changes In Xenobiotic Metabolismmentioning

confidence: 99%

“…MAFLD is associated with changes in the activity of some CYPs. For instance, human MALFD is frequently associated with reduced CYP3A4 activity and increased CYP2E1 activity [32][33][34][35]37,38]. Thus, the metabolism of drugs, such as troglitazone metabolized by CYP3A4 or acetaminophen by CYP2E1, as well as their hepatotoxicity profile, may be altered [39,40].…”

Section: Mafld and Changes In Xenobiotic Metabolismmentioning

confidence: 99%

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Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease

Massart¹,

Begriche²,

Corlu³

et al. 2022

IJMS

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Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver, steatohepatitis, cirrhosis and hepatocellular carcinoma. Besides nutritional and genetic factors, different xenobiotics such as pharmaceuticals and environmental toxicants are suspected to aggravate MAFLD in obese individuals. More specifically, pre-existing fatty liver or steatohepatitis may worsen, or fatty liver may progress faster to steatohepatitis in treated patients, or exposed individuals. The mechanisms whereby xenobiotics can aggravate MAFLD are still poorly understood and are currently under deep investigations. Nevertheless, previous studies pointed to the role of different metabolic pathways and cellular events such as activation of de novo lipogenesis and mitochondrial dysfunction, mostly associated with reactive oxygen species overproduction. This review presents the available data gathered with some prototypic compounds with a focus on corticosteroids and rosiglitazone for pharmaceuticals as well as bisphenol A and perfluorooctanoic acid for endocrine disruptors. Although not typically considered as a xenobiotic, ethanol is also discussed because its abuse has dire consequences on obese liver.

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“…( 1 ) In addition, FL has also been shown to impact hepatic drug‐metabolizing enzymes. ( 7 , 8 , 9 , 10 , 11 ) Specifically, evidence suggests that NAFLD is associated with increased activity of cytochrome P450 family 2 subfamily E member 1 (CYP2E1) and decreased activity of CYP3A4. ( 7 , 10 , 12 ) Altered activity of drug‐metabolizing enzymes in FL is predicted to affect drug pharmacokinetics and pharmacodynamics, but to date there is a paucity of data to show that these findings from basic research studies have clinically meaningful implications.…”

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confidence: 99%

Fatty Liver Is an Independent Risk Factor for Delayed Recovery from Anesthesia

et al. 2021

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Fatty liver (FL) is associated with altered activity of hepatic drug-metabolizing enzymes, but the clinical significance is unknown. Many anesthetic agents are metabolized in the liver. We aimed to determine whether FL impacts recovery from anesthesia as a surrogate for altered drug metabolism. This was a single-center, retrospective, case-control study of all adults who underwent anesthesia and concurrent abdominal imaging (n = 2,021) in a hospital setting. FL (n = 234) was identified through radiology reports. Anesthesia recovery, the primary endpoint, was defined by Aldrete's recovery score (RS, 0-10), assessed following postanesthesia care unit (PACU) arrival, with RS ≥8 considered discharge eligible. FL and controls were compared using univariate and multivariate analyses, adjusting for confounders. A secondary matched-pairs analysis matched FL and controls 1:1 for confounders. Time from airway removal to discharge eligibility was compared using multivariate Cox regression. On PACU arrival, 54.1% of FL were discharge eligible compared to 61.7% of controls (P = 0.03), with lower activity scores on univariate (P = 0.03) and multivariate analysis (P = 0.03). On matched-pairs analysis, discharge eligibility, activity, consciousness, and total RSs were lower in FL (P ≤ 0.04 for all). Median time from airway removal to discharge eligibility was 43% longer in FL (univariate, P = 0.01; multivariate hazard ratio, 1.32; P = 0.046). To further exclude confounding by obesity, we performed a sensitivity analysis limited to a body mass index <30, where FL was still associated with lower activity (P = 0.03) and total RS (P = 0.03). Conclusion:Patients with FL have delayed recovery from anesthesia, suggesting altered drug metabolism independent of metabolic risk factors. (Hepatology Communications 2021;0:1-12).

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Nonalcoholic Fatty Liver Disease (NAFLD) and Hepatic Cytochrome P450 (CYP) Enzymes

Cited by 37 publications

References 106 publications

Ovariectomy-Induced Hepatic Lipid and Cytochrome P450 Dysmetabolism Precedes Serum Dyslipidemia

Ovariectomy-Induced Hepatic Lipid and Cytochrome P450 Dysmetabolism Precedes Serum Dyslipidemia

Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease

Fatty Liver Is an Independent Risk Factor for Delayed Recovery from Anesthesia

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