Gender-Related Differences in Mouse Hepatic Ethanol Metabolism.

Kishimoto, Ritsuko; Ogishi, Yasuka; Ueda, Miwa; Matsusaki, Mari; Amako, Katumi; Goda, Katalin; Park, Sang‐Shin

doi:10.3177/jnsv.48.216

Cited by 23 publications

(16 citation statements)

References 40 publications

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“…in Adh mRNA levels (Tussey and Felder, 1989;Mezey et al, 2005;Gyamfi et al, 2006). The current findings are also consistent with several reports that hepatic ADH is more highly expressed in female rodents and in women (Maly and Sasse, 1991;Harada et al, 1998;Aasmoe and Aarbakke, 1999;Kishimoto et al, 2002).…”

Section: Discussionsupporting

confidence: 81%

“…hPXR Mice and Acute Ethanol Hepatotoxicity increases mitochondrial ALDH activity, consistent with the sexual dimorphisms in both ADH and ALDH expression seen in hPXR females in the current study (Kishimoto et al, 2002). Third, in humans and in Sprague-Dawley rats, EtOH ingestion leads to increased ER expression in males, not females (Colantoni et al, 2002).…”

Section: Discussionsupporting

confidence: 61%

“…Although peak BEC levels were similar between fasting male and female hPXR mice after a single EtOH dose, the rate of EtOH elimination was enhanced in female hPXR mice compared with males. Similarly, serum EtOH levels were lower in female C3H/HeNCrj mice after acute EtOH administration, with females exhibiting enhanced ADH and ALDH activity (Kishimoto et al, 2002). The phenomenon that women metabolize EtOH more rapidly than men has also been observed consistently in human subjects (Mishra et al, 1989;Jones, 2010).…”

Section: Discussionmentioning

confidence: 58%

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Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

Spruiell

Gyamfi

Yeyeodu

et al. 2015

J Pharmacol Exp Ther

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Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXRhumanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor a, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 58%

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Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

Spruiell

Gyamfi

Yeyeodu

et al. 2015

J Pharmacol Exp Ther

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“…10 Cyp4a and Cyp2e1 are regulated in a sex-dependent fashion such that Cyp4a is more heavily induced by PPAR␣ agonists in male compared with female mice, [23][24][25] whereas in some mouse strains, Cyp2e1 expression is higher in females compared with males. 26,27 To test whether gender differences account for the diminished role of Cyp2e1 in male mice fed the MCD diet, female littermates were fed the MCD or control diet for 5 weeks and Cyp2e1 protein levels were assessed in hepatic microsomal fractions. Consistent with results obtained by Leclercq et al, 10 there was a 2.7-fold increase (P ϭ .004) in Cyp2e1 protein in female mice fed the MCD diet compared with those fed the control diet, but there was no difference between Cyp2e1 protein levels in male mice fed the control compared with the MCD diet (P ϭ .9).…”

Section: Resultsmentioning

confidence: 99%

Central Role of Pparα–Dependent Hepatic Lipid Turnover in Dietary Steatohepatitis in Mice

et al. 2003

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We have proposed that steatohepatitis results from reactive oxygen species (ROS) acting on accumulated fatty acids to form proinflammatory lipoperoxides. Cytochrome P450 4a (Cyp4a) and Cyp2e1 are potential hepatic sources of ROS. We tested the hypothesis that increasing Cyp4a through activation of peroxisome proliferator-activated receptor ␣ (PPAR␣) should aggravate steatohepatitis produced by feeding a methionine and choline deficient (MCD) diet. Conversely, we assessed dietary steatohepatitis in PPAR␣ ؊/؊ mice that cannot up-regulate Cyp4a. Male wild type (wt) or PPAR␣ ؊/؊ mice (C57BL6 background) were fed the MCD diet with or without Wy-14,643 (0.1% wt/wt), a potent PPAR␣ agonist. Controls were fed the same diet supplemented with methionine and choline. After 5 weeks, wt mice fed the MCD diet developed moderate steatohepatitis and alanine aminotransferase (ALT) levels were increased. Wy-14,643 prevented rather than increased liver injury; ALT levels were only mildly elevated whereas steatohepatitis was absent. Wy-14,643 up-regulated mRNA for liver fatty acid binding protein and peroxisomal ␤-oxidation enzymes (acyl-CoA oxidase, bifunctional enzyme, and ketothiolase), thereby reducing hepatic triglycerides and preventing steatosis. In wt mice, dietary feeding up-regulated Cyp4a14 mRNA 2.7-fold and increased hepatic lipoperoxides compared with controls. Wy-14,643 prevented hepatic lipoperoxides from accumulating despite an 18-fold increase in both Cyp4a10 and Cyp4a14 mRNA. PPAR␣ ؊/؊ mice fed the MCD diet developed more severe steatohepatitis than wt mice, and were unaffected by Wy-14,643. In conclusion, PPAR␣ activation both increases Cyp4a expression and enhances hepatic lipid turnover; the latter effect removes fatty acids as substrate for lipid peroxidation and is sufficiently powerful to prevent the development of dietary steatohepatitis. (HEPATOLOGY 2003;38:123-132.)

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“…Importantly, whether EtOH-naı¨ve or -withdrawn, BAC was lower in GDX than in intact or GDX-ADX males and higher in GDX than in intact or GDX-ADX females. Given that the hepatic enzymes involved in EtOH metabolism are controlled by testosterone, estradiol and progesterone, their differential depletion by GDX in males or females would increase liver alcohol dehydrogenase activity and EtOH metabolism in males (Cicero et al, 1980;Mezey et al, 1980) and presumably reduce metabolism in females (Dettling et al, 2008;Kishimoto et al, 2002). Indeed, the differing magnitudes and durations of the hypothermic responses of the intact EtOH-naı¨ve males and females and their subsequent differential alterations after GDX reflect the sex differences in BAC at 180-minute after EtOH injection.…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Ethanol‐Induced Hypothermia in Ethanol‐Naïve and Ethanol‐Dependent/Withdrawn Rats

Taylor¹,

Tio²,

Bando³

et al. 2008

Alcoholism Clin & Exp Res

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Background: Human and animal findings indicate that males and females display major differences in risk for and consequences of alcohol abuse and alcoholism. These differences are in large part mediated by sex-specific hormonal environments. Gonadal and adrenal secretory products are known to modulate the neurobehavioral responses of ethanol (EtOH) dependence and withdrawal. However, the effects of these steroids on physiological adaptations, such as thermoregulation, are less well established. To study the role of sex-related hormones in mediating sex differences in the hypothermic response to acute challenge with EtOH, we compared the EtOHinduced hypothermic responses of EtOH-naı¨ve male and female rats and EtOH-dependent (on the third day of withdrawal) male and female rats before (intact) and after depletion of all gonadal and adrenal steroids by gonadectomy (GDX) with or without adrenalectomy (ADX).Methods: Intact and GDX male and female rats, with or without ADX, were fed an EtOHcontaining liquid diet for 15 days while control (EtOH-naı¨ve) rats were pairfed the isocaloric liquid diet without EtOH or fed normal rat chow and water. On the third day of withdrawal from the EtOH diet we tested the hypothermic response to EtOH challenge (1.5 g ⁄ kg BWt, ip). Blood alcohol content (BAC) and corticosterone (CORT) content were analyzed in a separate series of intact and GDX males and females with and without ADX in response to the EtOH challenge.Results: Ethanol-induced hypothermia was significantly greater and its duration significantly longer in intact males than females when subjects were EtOH-naı¨ve. EtOH-induced hypothermia was significantly greater in intact females than males by the third day of withdrawal from EtOH dependence. GDX in males significantly shortened the duration of the hypothermic response and tended to blunt EtOH-induced hypothermia while response duration was significantly extended by GDX in females that tended to enhance EtOH-hypothermia. EtOH-induced hypothermia was significantly enhanced and its duration significantly lengthened by combined GDX and ADX in EtOH-naı¨ve and -withdrawn males and by combined GDX and ADX in EtOH-naı¨ve but not EtOH-withdrawn females. These differential EtOH-induced hypothermic responses did not appear to be caused by differences in EtOH handling among the groups. The absence of adrenal activation by EtOH in the GDX-ADX males and females contributes to their enhanced EtOH-induced hypothermic responses.Conclusions: These results implicate the direct and indirect effects of removal of gonadal and adrenal secretory products as mediators of the thermoregulatory actions of EtOH.

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Gender-Related Differences in Mouse Hepatic Ethanol Metabolism.

Cited by 23 publications

References 40 publications

Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

Pregnane X Receptor–Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity

Central Role of Pparα–Dependent Hepatic Lipid Turnover in Dietary Steatohepatitis in Mice

Sex Differences in Ethanol‐Induced Hypothermia in Ethanol‐Naïve and Ethanol‐Dependent/Withdrawn Rats

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