The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes

Parkinson, Andrew; Mudra, Daniel R.; Johnson, Cory; Dwyer, A.; Carroll, Kathleen M.

doi:10.1016/j.taap.2004.01.010

Cited by 338 publications

(237 citation statements)

References 38 publications

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“…Of interest, there appears to be no sex difference for hepatic Cyp2E1 in humans. 55 While we did not measure Cyp2E1 activity from livers of the animals in our study, we did measure hepatic LDH, an enzyme indirectly involved with the gluconeogenic pathway.…”

Section: Evidence For Sex Differences In Hgn Capacitymentioning

confidence: 99%

Sex Differences in Hepatic Gluconeogenic Capacity After Chronic Alcohol Consumption

Sumida

Hill

Matveyenko³

2007

Clinical Medicine & Research

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Alcohol-induced hypoglycemia has traditionally been attributed to the amount of ethanol consumed rather than any inherent decline in glucose output capacity by the gluconeogenic organs and/or an increase in skeletal muscle glucose uptake. Further, while the potential for sex differences that might impact glucose homeostasis following chronic alcohol consumption has been recognized, direct evidence has been noticeably absent. This paper will provide a brief review of past and present reports of the potential for sex differences in glucose homeostasis following chronic ethanol consumption. This paper will also provide direct evidence from our laboratory demonstrating sex differences from chronic alcohol consumption resulting in a decrement in glucose appearance and more importantly, a specific decline in hepatic gluconeogenic (HGN) capacity in the absence and presence of ethanol. All our studies involved 8 weeks of chronic alcohol consumption in male and female Wistar rats, as well as a 24 to 48 hour fast to deplete hepatic glycogen stores. Under the conditions of chronic alcohol consumption and an acute dose of ethanol, we provide in vivo evidence of an early decline in whole body glucose appearance in females fed an ethanol diet compared to controls.While the decline was also observed in males fed the alcohol diet, it occurred much later compared to ethanol fed females. The site for the decline in whole body glucose production (i.e., either the kidneys or the liver) was beyond the scope of our prior in vivo study. In a follow-up study using the in situ perfused liver preparation, we provide additional evidence for a specific reduction in HGN capacity from lactate in ethanol fed females compared to ethanol fed males in the absence of alcohol in the perfusion medium. Finally, employing the isolated hepatocyte technique, we report decrements in HGN from lactate in ethanol fed females compared to ethanol fed males in the presence of ethanol in the incubation medium.The mechanism for the specific decline in HGN within the liver of ethanol fed females remains to be determined.To the extent that our observations in animals can be extrapolated to humans, we conclude that alcoholic women are more susceptible to ethanol-induced hypoglycemia compared to alcoholic men.

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Section: Evidence For Sex Differences In Hgn Capacitymentioning

confidence: 99%

Sex Differences in Hepatic Gluconeogenic Capacity After Chronic Alcohol Consumption

Sumida

Hill

Matveyenko³

2007

Clinical Medicine & Research

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“…The role of gender in the activities of some CYP450 enzymes is well established in many species, e.g., humans (Parkinson et al, 2004;Scandlyn et al, 2008), rats (Mugford and Kedderis, 1998), minipigs and conventional pigs (Skaanild and Friis, 1999;Zamaratskaia et al, 2006). Castration of Meishan male pigs resulted in increased mRNA, protein levels and activities of CYP1A enzymes (Kojima et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…p-Nitrophenol hydroxylation is often used as a marker of CYP2E1 (Koop et al, 1989;Sohn et al, 2001). In pigs, however, the selectivity of this substrate is somewhat questionable, given that in porcine liver microsomes, p-nitrophenol is partially metabolized by CYP2A (Skaanild, 2006).The role of gender in the activities of some CYP450 enzymes is well established in many species, e.g., humans (Parkinson et al, 2004;Scandlyn et al, 2008), rats (Mugford and Kedderis, 1998), minipigs and conventional pigs (Skaanild and Friis, 1999;Zamaratskaia et al, 2006). Castration of Meishan male pigs resulted in increased mRNA, protein levels and activities of CYP1A enzymes (Kojima et al, 2008).…”

mentioning

confidence: 99%

Modulation of porcine cytochrome P450 enzyme activities by surgical castration and immunocastration

Zamaratskaia

Žlábek

Chen

et al. 2009

Animal

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The present study aimed to evaluate some cytochrome P450 metabolic enzyme activities in hepatic microsomes prepared from entire male pigs (uncastrated pigs), surgically castrated pigs and pigs immunized against gonadotropin-releasing hormone (immunocastrated pigs). The activities of the following enzymes were measured: ethoxyresorufin O-deethylase (EROD, CYP1A1/ 1A2), methoxyresorufin O-deethylase (MROD, CYP1A2), pentoxyresorufin O-depentylase (PROD, CYP2B), coumarin hydroxylase (COH, CYP2A) and p-nitrophenol hydroxylase (PNPH, CYP2A/2E1). The total cytochrome P450 contents were not affected by either surgical or immunocastration. Hepatic microsomal activities for EROD, PROD, COH and PNPH were lower in entire male pigs compared with surgically castrated and immunocastrated pigs ( P , 0.05). Surgically and immunocastrated male pigs were similar with respect to EROD, MROD, PROD and COH activities ( P . 0.05), whereas surgically castrated pigs exhibited lower PNPH activity compared with immunocastrated pigs ( P 5 0.029). The effect of different concentrations of testicular steroidstestosterone, 17b-estradiol, free estrone and androstenone -on enzyme activities was evaluated by in vitro microsomal study. Testosterone at the concentration of 8 pmol/ml inhibited EROD activities and estradiol-17b at the concentration of 1.8 pmol/ml inhibited PROD activities in hepatic microsomes from surgically castrated pigs. The highest concentration of androstenone (7520 pmol/ml) inhibited COH activities, whereas a 42-fold lower concentration of androstenone (180 pmol/ml) stimulated COH activities in surgically castrated pigs. Both free estrone (3.5 pmol/ml) and androstenone (55 pmol/ml) inhibited EROD activities in microsomes from entire male pigs. Stimulation of COH activities by the highest dose of free estrone (18 pmol/ml) was recorded in microsomes from entire male pigs. However, these effects of steroids were not concentration-dependent and the maximum extent did not exceed 615% variation compared with the controls. There was no inhibition of PNPH activities in the hepatic microsomes from either entire or castrated pigs. In conclusion, we showed that EROD, PROD, COH and PNPH activities were lower in entire male pigs compared with those in surgically and immunocastrated pigs. Direct inhibition by the testicular steroids -testosterone, 17b-estradiol, free estrone and androstenone -was not the primary cause of the reduced enzyme activities.Keywords: castration, cytochrome P450, porcine liver microsomes, steroids ImplicationsThe present study evaluated some cytochrome P450 enzyme activities in liver microsomes from uncastrated male pigs, surgically castrated pigs and pigs immunized against gonadotropin-releasing hormone (immunocastrated pigs). We found that CYP1A1, CYP2A, CYP2B and CYP2E1 activities were lower in uncastrated male pigs compared with surgically castrated and immunocastrated pigs. These findings strengthen the hypothesis of testicular steroid involvement in cytochrome P450 enzyme regulation. The differences in the ac...

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“…Primary hepatocytes can be of use, but these cells dedifferentiate in culture. 12 Therefore, primary hepatocytes are not suited for long-term experiments. Other models have been proposed which make use of immortal human hepatoma cell lines that retain to some extent hepatocyte-specific function, especially CYP450 enzyme activities and their inducibility.…”

Section: Discussionmentioning

confidence: 99%

“…On the first glance, primary hepatocytes possess all the required activities and short-term studies can be performed with valid results. 11,12 Yet, primary hepatocytes dedifferentiate in culture dependent on the used culture conditions (plated monolayer, sandwich culture and suspension culture). This dedifferentiation process results in a loss in CYP450 activities and inducibility within few days.…”

mentioning

confidence: 99%

Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies

Benesic

Rahm

Ernst

et al. 2012

Laboratory Investigation

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Gender, ethnicity and individual differences in hepatic metabolism have major impact on individual drug response, adverse events and attrition rate during drug development. Therefore, there is an urgent need for reliable test systems based on human cells. Yet, the use of primary human hepatocytes (PHHs) is restricted by limited availability, invasive preparation and short-term stability in culture. All other cellular approaches proposed so far have major disadvantages. We investigated whether peripheral human monocytes after cultivation according to our novel protocol (monocyte-derived hepatocyte-like cells (MH cells)) can serve as an in vitro model for hepatocyte metabolism. Enzyme activities, synthesis parameters (coagulation factor VII and urea) and cytochrome (CY) P450 activities and induction were investigated. Furthermore, MH cells were compared with PHH from the same donor. Using our protocol, we could generate cells that exhibit hepatocyte-like properties: These cells show 71±9% of specific ALT activity, 41±3% of CYP3A4 activity and 65±13% of factor VII secretion when compared with PHHs. Consequently, CYP-mediated acetaminophen toxicity and drug interactions could be shown. Moreover, the investigated parameters were stable in culture over at least 4 weeks. Furthermore, MH cells retain gender-specific and donor-specific CYP activities and toxicity profiles, respectively. MH cells show quantitative and qualitative approximation to human hepatocytes concerning CYP-metabolism and toxicity. Our data support individual prediction of toxicity and CYP metabolism. MH cells are a novel tool to investigate long-term hepatic toxicity, metabolism and drug interactions. The liver is an important site of drug metabolism and hepatocytes are mainly responsible for toxification and detoxification of substances. A huge array of enzymes and transporters allows the hepatocyte to metabolize, conjugate and finally excrete xenobiotics and endobiotics. The first step, also referred to as phase-I metabolism, is performed predominantly by enzymes of the cytochrome P450 (CYP450) enzyme family. The CYPs 1A2, 2A6, 2B6, 2D6, 2E1, 3A4 and 3A5 are found in hepatocytes with great abundance. 1 Most CYP enzymes can be induced, that is, their activity in the hepatocyte is increased to manage greater amounts of xenobiotics. This induction is mediated by receptors, such as the pregnane-X-receptor (PXR), 2 the aryl-hydrocarbon receptor 3 and the constitutive androestendione receptor. 1 Knowing the way a substance is metabolized and how a substance interacts with co-medication is crucial for modern drug design. Therefore, hepatocyte models are urgently needed for drug development, because no other cell possesses a comparable equipment of metabolism pathways. The complexity of this system is augmented by different activities of CYP enzymes dependent on sex, age, ethnicity and individual factors, including co-medication. [4][5][6][7] Pharmacogenomics is a powerful tool to identify different individual metabolism patterns, 8 yet this method only d...

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The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes

Cited by 338 publications

References 38 publications

Sex Differences in Hepatic Gluconeogenic Capacity After Chronic Alcohol Consumption

Sex Differences in Hepatic Gluconeogenic Capacity After Chronic Alcohol Consumption

Modulation of porcine cytochrome P450 enzyme activities by surgical castration and immunocastration

Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies

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