Increased expression of cytochrome P450 IIIA2 in male rat liver after dietary vitamin A supplementation

Murray, Michael T.; Cantrill, Elizabeth; Martini, Robert; Farrell, Geoffrey C.

doi:10.1016/0003-9861(91)90089-2

Cited by 36 publications

(13 citation statements)

References 30 publications

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“…Liver P450 enzymes have been shown to metabolize retinol and retinoic acid to polar metabolites (68,72), and the administration of vitamin A, canthaxanthin (a non-provitamin A carotenoid), or a beta-carotene metabolite (β-apo-8 -carotenal) has been shown to induce P450s in laboratory animals (5,22,55). In one recent study, CYP1A1, CYP1A2, and other corresponding P450 genes, which would predispose an individual to cancer risk from the widely bioactivated tobacco smoke procarcinogens (i.e.…”

Section: Cytochromes P450 and Cyp Genesmentioning

confidence: 99%

Nutrition, Genetics, and Risks of Cancer

Rock

Lampe

Patterson

2000

Annu. Rev. Public Health

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diets Abstract Dietary patterns, nutrients, and other constituents of food are major components of the environmental influences that contribute to risk for cancer, and the study of interactions between nutritional and genetic factors is a new and important area of research. This review describes the concepts and principles underlying this area of study and types of relationships between nutritional and genetic factors, and it provides examples of specific diet-gene interactions that are of current interest, with an emphasis on implications for cancer prevention and public health. Polymorphisms exist in the genes for the activating and conjugating metabolizing enzymes, and the induction of metabolizing enzyme activity by nutritional factors may result in either the activation of a carcinogen or the detoxification of a reactive intermediate metabolite. The relationship between the methylenetetrahydrofolate reductase gene and dietary folate is an example of a diet-gene interaction that involves a polymorphism in a vitamin metabolism gene, and the presence of the variant appears to influence both risk for cancer and folate requirements. Diet-gene interactions likely contribute considerably to the observed inter-individual variations in cancer risk in response to exposures to the nutritional factors that have the potential to promote or protect against cancer. Insights into mechanisms by which nutritional factors affect the process of carcinogenesis are provided by knowledge of the targeted gene function and enzyme activity. Increased knowledge in this area will allow a more refined approach to reducing risk for cancer, with diet interventions targeted toward individuals and subgroups that are genetically susceptible and responsive to the effects of nutritional factors.Investigating the cellular and molecular pathogenesis of cancer is an established and important area of basic science research. Within the past several years, the capability of examining biomarkers of various genetic factors in the development and progression of chronic diseases, such as cancers, has enabled researchers to study these factors in clinical and community-based populations, in which environmental factors can also be measured or even manipulated.

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Section: Cytochromes P450 and Cyp Genesmentioning

confidence: 99%

Nutrition, Genetics, and Risks of Cancer

Rock

Lampe

Patterson

2000

Annu. Rev. Public Health

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“…The male primarily metabolizes various 3-keto-4-ene steroids such as progesterone (PROG), 1 TEST, and 4-AN into the two oxidized products, 16␣-OH (in some cases, 2␣-OH also) and 6␤-OH products, mainly by the respective, malespecific cytochrome P450 subforms (P450s), CYP2C11 and CYP3A2, whereas the female metabolizes them primarily into the 5␣-reduced products by female-predominant 5␣-reductase (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Expressions of these sexually differentiated enzyme activities are largely regulated at the transcription level under endocrine control, with the secretory pattern of GH playing a major role.…”

mentioning

confidence: 99%

Self-augmentation Effect of Male-specific Products on Sexually Differentiated Progesterone Metabolism in Adult Male Rat Liver Microsomes

Yamada¹,

Yamada²,

Fujita³

et al. 2001

Journal of Biological Chemistry

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It is well known that several 3-keto-4-ene steroids such as progesterone and testosterone are metabolized in a gender-specific or -predominant manner by adult rat liver microsomes. In the male, these steroids are primarily metabolized into two oxidized (16␣-hydroxyl and 6␤-hydroxyl) products mainly by the respective, male-specific cytochrome P450 subforms, CYP2C11 and CYP3A2, while they are primarily metabolized into the 5␣-reduced products by female-predominant 5␣-reductase in the female. These sexually differentiated enzyme activities are largely regulated at the transcription level under endocrine control. In the present study, we show that unlabeled 16␣-hydroxyprogesterone and 6␤-hydroxyprogesterone inhibited the 5␣-reductive [ 3 H]progesterone metabolism by adult male rat liver microsomes without significantly inhibiting the CYP2C11 and CYP3A2 activities producing themselves, whereas 3␣-hydroxy-5␣-pregnan-20-one and 5␣-pregnane-3,20-dione not only stimulated the 5␣-reductive metabolism producing themselves but also inhibited the male-specific oxidative metabolism. This finding compels us to propose a novel hypothesis that adult male rat liver microsomes may possess a self-augmentation system regulated by the male-specific products on sexually differentiated steroid metabolism, besides regulation by gene expressions of the related enzymes.It is well established that activities of many steroid-metabolizing enzymes in adult rat liver microsomes are sexually differentiated. The male primarily metabolizes various 3-keto-4-ene steroids such as progesterone (PROG), 1 TEST, and 4-AN into the two oxidized products, 16␣-OH (in some cases, 2␣-OH also) and 6␤-OH products, mainly by the respective, malespecific cytochrome P450 subforms (P450s), CYP2C11 and CYP3A2, whereas the female metabolizes them primarily into the 5␣-reduced products by female-predominant 5␣-reductase (1-10). Expressions of these sexually differentiated enzyme activities are largely regulated at the transcription level under endocrine control, with the secretory pattern of GH playing a major role. Intermittent and pulsatile (i.e. male pattern) GH secretion induces CYP2C11 gene expression, whereas a more continuous female pattern represses CYP2C11 and CYP3A2 gene expressions and conversely induces 5␣-reductase gene expression (6, 8 -10). Furthermore, sex hormones are thought to affect indirectly these gene expressions by acting on the hypothalamo-pituitary axis that controls the sexually dimorphic pattern of GH secretion (1-3, 6, 7).In the course of our investigation on structural requirements of substrates and/or inhibitors for active sites of CYP2C11 and CYP3A2 in male rat liver microsomes (to be published elsewhere), we unexpectedly found that male-specific products, 16␣-OH-P and 6␤-OH-P, inhibited female-predominant [ 3 H]PROG 5␣-reductase activity without significantly inhibiting the CYP2C11 and CYP3A2 activities producing themselves, while 3␣-OH-5␣-P and 5␣-P, female-predominant products by the 5␣-reductase, not only stimulated this enzyme acti...

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“…Other studies have shown that when rats were given a diet high in VA, they had increased levels of total cytochrome P450 (Leo et al, 1984). VA treatment also induces P4502C7 isozyme in primary rat hepatocytes (Westin et al, 1993) and P450IIIA2 in rat liver (Murray et al, 1991). Induction of cytochrome P450IIE1 by VA pretreatment can result in an increased bioactivation of VDC, resulting in an increase in the amount of toxic metabolites that cause damage to hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Vitamin A Potentiation of Vinylidene Chloride Hepatotoxicity in Rats and Precision-Cut Rat Liver Slices

et al. 1996

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(1996). Fundam. Appl. Toxicol. 34,[73][74][75][76][77][78][79][80][81][82][83] Pretreatment of large doses of vitamin A (VA) is known to potentiate the hepatotoxicity of carbon tetrachloride. Therefore the effects of 1-day VA pretreatment on VDC hepatotoxicity was examined both in vivo and in an in vitro system of precision-cut rat liver slices. Male Sprague-Dawley rats were pretreated with 250,000 IU/kg VA by oral gavage. After 24 hr rats were administered 50,100, or 200 mg/kg VDC ip. Precision-cut liver slices were prepared from VA pretreated rats 24 hr later and the liver slices were exposed for 2-8 hr to 0.025-1.0 fjl VDC evaporated into the gas phase of the incubation vials. VA pretreatment resulted in an enhancement of VDC toxicity, both in vivo and in vitro. There was a dose-dependent increase in plasma ALT 24 hr after VDC treatment of rats and an increase in K + leakage from liver slices after VDC exposure. Histologjcal analysis of the liver or the liver slices revealed that VA + VDC treatment resulted in centrilobular necrosis of the liver. When GdCl 3 (10 mg/kg iv) was administered just before VA pretreatment of rats, VDC toxicity was partially reversed as observed by a decrease in ALT in vivo and a decrease in the loss of K + in vitro. These results indicated that Kupffer cells, the resident macrophages of the liver, were partially responsible for the VA-potentiated VDC hepatotoxicity. One-day pretreatment of VA induced cytochrome P450IIE1 protein content as well as its enzymatic activity as measured by pnitrophenol hydroxylation. Because VDC is bioactivated by cytochrome P450IIE1, the increase in VDC hepatotoxicity after VA may be due to an increased bioactivation of VDC in the liver and in precision-cut liver slices. Thus, more than one mechanism may be involved in the VA enhancement of VDC hepatotoxicity.

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Increased expression of cytochrome P450 IIIA2 in male rat liver after dietary vitamin A supplementation

Cited by 36 publications

References 30 publications

Nutrition, Genetics, and Risks of Cancer

Nutrition, Genetics, and Risks of Cancer

Self-augmentation Effect of Male-specific Products on Sexually Differentiated Progesterone Metabolism in Adult Male Rat Liver Microsomes

Vitamin A Potentiation of Vinylidene Chloride Hepatotoxicity in Rats and Precision-Cut Rat Liver Slices

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