Genetic factors influence ethanol-induced uroporphyria in Hfe (—/—) mice

Gorman, Nadia; Trask, Heidi W.; Bement, William J.; Szakacs, Juliana G.; Elder, George H.; Balestra, Dominic J.; Jacobs, Nicholas J.; Jacobs, Judith M.; Sinclair, Jacqueline F.; Gerhard, Glenn S.; Sinclair, Peter R.

doi:10.1002/hep.1840400425

Cited by 4 publications

(5 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The finding that the response of mice to EtOH is strain‐specific is consistent with a previous study in which EtOH has been shown to cause uroporphoryria in alcohol‐treated Hfe knockout 129S6/SvEvTac mice but not in Hfe knockout mice with a C57BL/6 background (Gorman et al, 2004). Although in those studies the Hfe knockout in the 129 strain was more sensitive to the effect of alcohol in producing uroporphyria, this effect may not have been mediated by iron, as alcohol is known to induce 5‐aminolevulinic synthase, a rate‐limiting enzyme in porphyrin synthesis.…”

Section: Discussionsupporting

confidence: 91%

Effects of Alcohol Consumption on Iron Metabolism in Mice with Hemochromatosis Mutations

Flanagan

Peng

Beutler

2006

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

The effect of alcohol on iron homeostasis is dependent on the genetic background in mice. In an alcohol-susceptible strain, mutation of the Hfe gene diminished the response of the measured iron indices to alcohol treatment. This indicates that either maximal suppression of hepcidin levels had already occurred as a result of the Hfe mutation or that Hfe was a component of the pathway utilized by EtOH in suppressing hepcidin production and increasing iron absorption.

show abstract

Section: Discussionsupporting

confidence: 91%

Effects of Alcohol Consumption on Iron Metabolism in Mice with Hemochromatosis Mutations

Flanagan

Peng

Beutler

2006

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

show abstract

“…Effect of Withdrawal from EIP on Hepatic Levels of CYP2E1, CYP3A, and CYP1A2. Alcohol has been shown in rodents to increase hepatic levels of three P450s involved in APAP activation, CYP2E1, CYP3A, and CYP1A2 (Louis et al, 1994;Roberts et al, 1995;Gorman et al, 2004). In all studies investigating alcoholmediated APAP hepatotoxicity, the alcohol-containing liquid diets are withdrawn 11 to 24 h before administration of APAP to ensure complete clearance of alcohol from the blood, because blood ethanol levels as low as 5 mM protect animals from APAP hepatotoxicity (Thummel et al, 1988).…”

Section: Resultsmentioning

confidence: 99%

“…However, we have found that alcohol pretreatment increases APAP hepatotoxicity in Cyp2e1(Ϫ/Ϫ) mice, showing that CYP2E1 is not essential in the alcohol effect (Sinclair et al, 2000c). In other animal studies, alcohol has been reported to also increase CYP3A and CYP1A2 in the liver (Louis et al, 1994;Roberts et al, 1995;Gorman et al, 2004). Human consumption of alcoholic beverages is also associated with increases in CYP3A (Hoshino and Kawasaki, 1995;Niemelä et al, 1998).…”

mentioning

confidence: 85%

Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

Wolf¹,

Wood²,

Allard³

et al. 2007

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

ABSTRACT:CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(؊/؊) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(؊/؊) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity. We found that EIP-mediated increases in APAP hepatotoxicity occurred at lower APAP doses in wild-type mice (300 mg/kg) than in Cyp2e1(؊/؊) mice (600 mg/kg). Although this result suggests that CYP2E1 has a role in the different susceptibilities of these mouse lines, our findings that EIP-mediated increases in CYP3A activities were greater in wild-type mice compared with Cyp2e1(؊/؊) mice raises the possibility that differential increases in CYP3A may also contribute to the greater APAP sensitivity in EIP-pretreated wild-type mice. At the time of APAP administration, which followed an 11 h withdrawal from the alcohols, alcohol-induced levels of CYP3A were sustained in both mouse lines, whereas CYP2E1 was decreased to constitutive levels in wild-type mice. The CYP3A inhibitor triacetyloleandomycin (TAO) decreased APAP hepatotoxicity in EIP-pretreated wild-type and Cyp2e1(؊/؊) mice. TAO treatment in vivo resulted in inhibition of microsomal CYP3A-catalyzed activity, measured in vitro, with no inhibition of CYP1A2 and CYP2E1 activities. In conclusion, these findings suggest that both CYP3A and CYP2E1 contribute to APAP hepatotoxicity in alcohol-treated mice.Acetaminophen (APAP) is considered to be a relatively safe drug and is widely prescribed and used for its analgesic and antipyretic properties. The first reports of hepatotoxicity in humans resulting from APAP overdose were in 1966 ( Thomson and Prescott, 1966). Today, APAP is a frequent cause of liver failure and the leading cause of death due to accidental and deliberate overdose (for review, see Bromer and Black, 2003). APAP is mainly glucuronidated and sulfated in the liver by phase II metabolic pathways, leading to excretion of the drug. However, APAP is also metabolized by certain forms of cytochromes P450 (P450s) to N-acetyl-p-benzoquinone imine (NAPQI), a highly electrophilic metabolite that is considered to be responsible for triggering the ensuing liver damage. CYP1A2, CYP2E1, and CYP3A are three forms of rat and human P450s active in the conversion of APAP to NAPQI, with CYP2E1 and CYP3A having greater intrinsic activity than CYP1A2 (Patten et al., 1993;Thummel et al., 1993). Reduced glutathione (GSH) reacts with NAPQI, resulting in the inactivation of this reactive metabolite. When GSH levels become depleted, liver damage can occur as a result of the

show abstract

“…Some of these may be important in iron homeostasis. The sensitivity of 129S6/SvEvTAC mice to alcohol is greatly increased by the presence of the Hfe -/null gene, causing deposition of iron, but C57BL/6J mice with the same null gene inserted are resistant (161). The sensitivities of inbred strains of mice to uroporphyria induced by iron alone do not correlate with the Ahr genotype, despite the fact that DBA/2 mice remain the most insensitive, whereas an outbred strain gives a range of responses compatible with a variety of genetic factors being involved (145).…”

Section: Genetic Factors In Humansmentioning

confidence: 99%

Complex Gene−Chemical Interactions: Hepatic Uroporphyria As a Paradigm

Smith

Elder

2010

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

Many toxicological disorders, in common with numerous human diseases, are probably the consequence of multigene interactions with a variety of chemical and physiological factors. The importance of genetic factors may not be obvious initially from association studies because of their complexity and variable penetrance. The human disease, porphyria cutanea tarda (PCT), is a skin disease caused by the photosensitizing action of porphyrins arising secondary to the decreased activity of an enzyme of heme biosynthesis, uroporphyrinogen decarboxylase (UROD), in the liver. It is triggered by idiosyncratic hepatic interaction between genetic factors and chemicals such as alcohol, estrogenic drugs, and polyhalogenated aromatics. PCT and its animal models are known collectively as the hepatic uroporphyrias. There is strong evidence for the participation of iron in the pathogenesis of these conditions. Mouse models have been used to explore the relative importance of a variety of agents such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alcohol, and iron in the development of uroporphyria and to elucidate the mechanism of the depression of hepatic UROD activity. Mutations of the UROD and hemochromatosis (HFE) genes are genetic factors in some PCT patients which can be mimicked in mice heterozygous for the Hfe and Urod null genes. Association studies of uroporphyria induced by TCDD or hexachlorobenzene with DNA markers in mouse intercrosses have shown the participation of other, unknown, genetic factors in addition to the strong influence of the Ahr gene. The pathogenesis of hepatic uroporphyrias exemplifies the complexity of the interactions between chemical and genetic factors that can contribute to the hepatotoxicity of chemicals.

show abstract

Genetic factors influence ethanol-induced uroporphyria in Hfe (—/—) mice

Cited by 4 publications

References 30 publications

Effects of Alcohol Consumption on Iron Metabolism in Mice with Hemochromatosis Mutations

Effects of Alcohol Consumption on Iron Metabolism in Mice with Hemochromatosis Mutations

Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

Complex Gene−Chemical Interactions: Hepatic Uroporphyria As a Paradigm

Contact Info

Product

Resources

About