Constitutive and Inducible Expression of Hepatic CYP2E1 in Leptin-deficient ob/ob Mice

Leclercq, Isabelle; Field, Jacqueline; Enriquez, Annabelle; Farrell, Geoffrey C.; Robertson, Graham

doi:10.1006/bbrc.2000.2125

Cited by 64 publications

(53 citation statements)

References 38 publications

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“…Other factors such as difference of AOM metabolism were also evaluated between KK-A y and C57BL/6J mice. To this end, activities of CYP2E1, 24 the main enzyme that metabolizes AOM, were calculated and similar CYP2E1 activities were observed between KK-A y and C57BL/6J mice (Supporting Information Table S4). …”

Section: Carcinogenesismentioning

confidence: 90%

High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐A^y mice

Teraoka¹,

Mutoh

Takasu³

et al. 2010

Intl Journal of Cancer

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Obesity is associated with colon carcinogenesis. However, not much information is available regarding the mechanisms of obesity-associated colorectal cancer, and there are only few useful animal models for investigating the underlying mechanism between obesity and colorectal cancer. KK-A y mice exhibit severe obesity. Amount of visceral fat assessed by micro-computed tomography was almost 15 times higher than that of same aged C57BL/6J mice. Treatment with azoxymethane (AOM; 200 lg/mouse injected once a week for 3 times) resulted in markedly increased colon aberrant crypt foci (ACF) development (%70 ACF/mouse) in KK-A y mice compared with lean C57BL/6J mice (%9 ACF/mouse). Moreover, administration of AOM at a dose of 200 lg/mouse once a week for 6 times developed colorectal adenocarcinomas within only 7 weeks after the last AOM injection. The incidence of adenocarcinoma was 88% in KK-A y mice and was markedly higher than the 4% observed in C57BL/6J mice. The number of tumors/mouse was 7.80 in KK-A y mice and also markedly higher than the 0.12 in the C57BL/6Jcase. Interestingly, adenocarcinomas were observed in most of the AOM-treated KK-A y mice along with remarkable tumor angiogenesis, and some showed submucosal invasion. These results indicate that the KK-A y mouse, featuring intact leptin and leptin receptor Ob-Rbl, could be a useful animal model to investigate obesity-associated cancer.Epidemiological studies have suggested that metabolic syndrome, characterized by hyperglycemia, hyperinsulinemia, hyperlipidemia and hypertension, is a risk factor for colorectal cancer.

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Section: Carcinogenesismentioning

confidence: 90%

High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐A^y mice

Teraoka¹,

Mutoh

Takasu³

et al. 2010

Intl Journal of Cancer

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“…Among the possibilities is the potential influence of ␤-catenin on a transcriptional coactivator required for Cyp2e1 activation by Hnf1␣ or a micro RNA that destabilizes the CYP2E1 mRNA or alters its translation. Others observed an effect of leptin on constitutive levels of CYP2E1 mRNA in ob/ob mice, although Hnf1␣ expression was not determined (Leclercq et al, 2000b).…”

Section: Ethanol-inducible Cyp2e1mentioning

confidence: 95%

Cyp2e1

Gonzalez

2006

Drug Metab Dispos

190

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ABSTRACT:Bernard B. Brodie's laboratory was the first to examine the mechanisms of drug-induced toxicity at the molecular level. They found that acetaminophen hepatotoxicity was due to the metabolic activation of the drug to a highly reactive toxic metabolite that depleted cellular glutathione and covalently bound to protein. Subsequent studies revealed that activation of acetaminophen to an active metabolite is primarily carried out by CYP2E1, an ethanolinducible cytochrome P450 that was first suggested by characterization of the microsomal ethanol oxidation system. CYP2E1 is developmentally regulated, under liver-specific control, and undergoes substrate-induced protein stabilization. It is also regulated by starvation and diabetes through insulin-dependent mRNA stabilization. In addition to acetaminophen, CYP2E1 metabolically activates a large number of low M r toxicants and carcinogens and thus is of great toxicological importance. The mechanism of regulation CYP2E1 and its role in acetaminophen toxicity will be discussed.I am delighted and honored to be a recipient of the Bernard B. Brodie award. Like Brodie, I have spent my career at the National Institutes of Health. Other than our mutual interest in xenobiotic metabolism, the similarities end. Brodie was a pioneer in drug metabolism and toxicity and the concepts he generated during the course of his career are still of major importance in the development and use of drugs, and in the fields of dietary and environmental toxicology. Brodie led the transition of the field of classical physiological-based pharmacology into biochemical pharmacology where mechanism of drug action and toxicity could be determined. In particular, he noted that drug-induced toxicities can be due to dose-dependent production of highly reactive and unstable intermediates that covalently bind to cellular macromolecules. These concepts laid the foundations for subsequent studies including the enzymology, purification, and cloning of drug-metabolizing enzymes and, more recently, the production of genetically modified mice that were used to reveal the in vivo role of P450s and other drug-metabolizing enzymes in chemical toxicities. Among the most important P450s involved in chemical toxicities is CYP2E1. Ethanol-Inducible CYP2E1CYP2E1 has been extensively studied for many years because of its relevance to chemical toxicity and carcinogenicity. It is also conserved in mammals; although there are a number of single nucleotide polymorphisms in the CYP2E1 gene, there are no known polymorphisms that are the result of inactive CYP2E1 genes in humans or any animal models, and there are no large differences in catalytic activity among humans, rabbits, rats, and mice. This suggests that CYP2E1 has an important function in mammals.The Microsomal Ethanol Oxidation System and CYP2E1. The finding that microsomal membrane fractions are capable of catalyzing the oxidation of ethanol, designated the microsomal ethanol-oxidizing system (MEOS), was the first indication of the presence of an ethanol oxidi...

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“…48 Leptin treatment has been reported to increase the hepatic CYP2E1 expression in the ob/ob mutant mice. 49 The CYP2E1 activity that may increase due to AOM exposure and hyperleptinemia may therefore contribute to a higher incidence of putative precancerous lesions (ACF and BCACs) for CRC in the db/db mice. The inhibitory effects of CUSM on the development of putative precancerous lesions may be partly caused by influencing the hepatic and intestinal CYP2E1 activity, 50 but the content of fiber and/or pectin in the CUSMcontaining diets was too low to exert their biological effects.…”

Section: Discussionmentioning

confidence: 99%

Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice

Suzuki

Kohno

Yasui

et al. 2006

Intl Journal of Cancer

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The modulatory effects of dietary citrus unshiu segment membrane (CUSM) on the occurrence of aberrant crypt foci (ACF) and b-catenin accumulated crypts (BCACs) were determined in male C57BL/KsJ-db/db (db/db) mice initiated with azoxymethane (AOM). Male db/db, db/þ and þ/þ mice were given 5 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then they were fed the diet containing 0.02%, 0.1% or 0.5% CUSM for 7 weeks. At Week 12, a significant increase in the numbers of ACF and BCAC was noted in the db/db mice in comparison with the db/ þ and þ/þ mice. Feeding with CUSM caused reduction in the frequency of ACF in all genotypes of mice and the potency was high in order of the db/db mice, db/þ mice and þ/þ mice. The number of BCACs was also reduced by feeding with CUSM, thus resulting in a 28-61% reduction in the db/db mice, possibly due to suppression of cell proliferation activity in the lesions by feeding with CUSM-containing diet. Clinical chemistry revealed a low serum level of triglyceride in mice fed CUSM. In addition, CUSM feeding inhibited fatty metamorphosis and fibrosis in the liver of db/db mice. Our findings show that CUSM in the diet has a chemopreventive ability against the early phase of AOM-induced colon carcinogenesis in the db/db as well as db/þ and þ/þ mice, indicating potential use of CUSM in cancer chemoprevention in obese people. ' 2006 Wiley-Liss, Inc.Key words: citrus unshiu segment membrane; ACF; BCAC; colon carcinogenesis; db/db mice The modern Western lifestyle, including a high caloric intake, high-fat diets and physical inactivity, results in a positive energy balance, diabetes and obesity. These lifestyle patterns might also be risk factors for the development of colorectal cancer (CRC), 1 which is one of the major causes of morbidity and mortality in the Western world. 2 This malignancy has also increased in Asia owing to the changes in lifestyle, such as the dietary habit of increased meat consumption. 2,3 Several prospective and case-control studies have addressed the relationship between obesity/diabetes and CRC. 1,4,5 C57BL/KsJ-db/db (db/db) mice are used as a genetically altered animal model with genotypes of obesity and diabetes mellitus. 6 A disruption of the leptin receptor (Ob-R) gene in these mice leads to an over-expression of leptin in the adipose tissue and a concomitantly high serum concentration of leptin. 7,8 The synthesis of leptin in adipocytes is influenced by insulin, 9 tumor necrosis factor-a, 10 glucocorticoids, 11 reproductive hormones 12 and prostaglandins 13 that may be involved in the neoplastic processes. 14 In addition, leptin can act as a growth factor in colonic epithelial cells 15 while modulating the proliferation of colonic cryptal cells. 16 In contrast, more leptin in the blood clearly decreased colon carcinogenesis in 3 different animal models. 17,18 Thus, leptin might be one of the biological factors involved in the development of CRC associated with obesity/diabetes. The db/db mouse, therefore, is a very useful model for elucidating ...

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Constitutive and Inducible Expression of Hepatic CYP2E1 in Leptin-deficient ob/ob Mice

Cited by 64 publications

References 38 publications

High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐A^y mice

High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐A^y mice

Cyp2e1

Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice

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Constitutive and Inducible Expression of Hepatic CYP2E1 in Leptin-deficient ob/ob Mice

Cited by 64 publications

References 38 publications

High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐Ay mice

High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐Ay mice

Cyp2e1

Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice

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Product

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High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐A^y mice

High susceptibility to azoxymethane‐induced colorectal carcinogenesis in obese KK‐A^y mice