Cellular localization of hepatic cytochrome 1B1 expression and its regulation by aromatic hydrocarbons and inflammatory cytokines

Piscaglia, Fabio; Knittel, Thomas; Kobold, Dominik; Barnikol-Watanabe, Shitsu; Rocco, P. Di; Ramadori, Giuliano

doi:10.1016/s0006-2952(99)00066-0

Cited by 47 publications

(27 citation statements)

References 38 publications

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“…Cytokines generally have an inhibitory effect on CYP gene expression, whereas TNF-α enhances CYP1B1 expression, indicating that CYP1A and 1B expression levels are specifically regulated in relation to stimulants. 15) In the present study, higher expres- sion levels of the CYP1B1 gene were observed in 44.4% of HCC patients. Increased expression of CYP1B1 is observed in a wide range of human tumors.…”

Section: Discussionsupporting

confidence: 52%

Cytochrome P450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver

et al. 2004

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Cytochromes P450 (CYPs) compose a superfamily of similar proteins involved in detoxification and elimination, as well as activation of a wide variety of compounds. Most CYP family members are localized in the liver. In order to assess whether peripheral blood leukocytes (PBL) are available as a surrogate for the determination of CYP gene expression levels in the liver, we compared CYP gene expression levels in PBL with those in liver tissues from patients with hepatocellular carcinoma (HCC). We measured CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 3A4, 3A5, etabolism of foreign compounds in the body to polar, hydrophilic metabolites is an important prerequisite for detoxification and elimination of xenobiotics from the body. The cytochromes P450 (CYPs) are a superfamily of similar heme-containing proteins that are involved in the oxidative metabolism of xenobiotics. CYPs also catalyze the bioactivation and inactivation of a wide variety of endogenous compounds, including steroid hormones and eicosanoids. Most of the CYP family members are located in the liver.1-3) Many environmental factors, stress, drugs and diseases influence the expression levels of CYP family members, which may lead to alterations of hepatic drug metabolism in man. Studies on such alterations generally require systemic administration of a drug or probe substance and the application of standard pharmacokinetic approaches. 4,5) Although small amounts of needle biopsy material from the liver can be used for assessment of gene expression, the process of biopsy is accompanied by practical and ethical problems. Some CYPs are also expressed in extra-hepatic tissues such as the lung, the kidney and the small intestine. Although xenobiotics are transported via the blood and peripheral blood is obtained for routine medical examination, little is known about CYP expression in peripheral blood cells. So far, CYP1A1, 1B1, 2D6, 2E1 and 3A genes have been shown to be expressed in peripheral blood.6, 7) In order to determine whether peripheral blood leukocytes (PBL) are applicable as a surrogate for assessment of CYP gene expression in the liver, we measured CYP gene expression levels in PBL and the liver, and studied the intra-individual correlation between them. Approximately 70% of human liver CYPs is accounted for by CYP1A2, 2A6, B6, 2C, 2D6, 2E1 and 3A.8) Here, we measured the expression levels of 19 CYP genes, i.e., CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 3A4, 3A5, 3A7, 4A11, 4B1 and CYP27, by real-time reverse-transcription (RT)-PCR. Furthermore, we compared the CYP gene expression levels in tumor and non-tumor tissues from liver cancers to assess whether carcinogenesis is associated with specific changes in CYP gene expression levels or not. Materials and MethodsWe investigated 18 patients with hepatocellular carcinoma (HCC), 2 patients with intrahepatic cholangiocarcinoma (ICC), 2 with bile duct cancer (BDK) and 1 with colon cancer metastasized to the liver (META) who underwent surgical r...

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Section: Discussionsupporting

confidence: 52%

Cytochrome P450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver

et al. 2004

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“…A rise in CYP1B1 mRNA levels was noted as early as after 4 h of incubation with benzo[a]pyrene, with the effect being more pronounced after longer incubations. This is again consistent with previous studies employing rat hepatocytes where CYP1B1 mRNA levels were elevated following exposure to polycyclic aromatic hydrocarbons (Piscaglia et al, 1999). Clearly, although CYP1B1 is poorly expressed in the liver, it is inducible, at least at the mRNA level, in response to xenobiotic exposure.…”

Section: Discussionsupporting

confidence: 92%

Evaluation of the precision-cut liver and lung slice systems for the study of induction of CYP1, epoxide hydrolase and glutathione S-transferase activities

et al. 2007

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“…What little CYP1B1 there is in liver is localized to hepatic stellate cells and myofibroblasts, i.e., mesenchymal (Piscaglia et al, 1999), instead of parenchymal, as found for CYP1A2 and inducible CYP1A1 and CYP1A2 (Dey et al, 1999). CYP1B1 is inducible by UV in skin (Katiyar et al, 2000) and also exists in blood monocytes and macrophages (Baron et al, 1998).…”

Section: Discussionmentioning

confidence: 93%

Oral Exposure to Benzo[a]pyrene in the Mouse: Detoxication by Inducible Cytochrome P450 Is More Important Than Metabolic Activation

Uno

Dalton²,

Derkenne³

et al. 2004

Mol Pharmacol

291

263

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The cytochrome P450 (CYP1A1) enzyme metabolically activates many polycyclic aromatic hydrocarbons, including benzo [a]pyrene (BaP), to DNA-and protein-binding intermediates that are associated with toxicity, mutagenesis, and carcinogenesis. As a result, it is widely accepted that CYP1A1 potentiates the toxicity of this class of chemicals. In distinct contrast, we show here that CYP1A1 inducibility is essential in the detoxication of oral BaP. We compared Cyp1a1(Ϫ/Ϫ) knockout mice, having the genetic absence of the CYP1A1 enzyme, with Cyp1a1(ϩ/ϩ) wild-type mice. At an oral BaP dose of 125 mg/ kg/day, Cyp1a1(Ϫ/Ϫ) mice died within 30 days whereas Cyp1a1(ϩ/ϩ) mice displayed no outward signs of toxicity. The rate of BaP clearance was 4-fold slower in Cyp1a1(Ϫ/Ϫ) than Cyp1a1(ϩ/ϩ) mice. The cause of death in Cyp1a1(Ϫ/Ϫ) mice receiving oral BaP seemed to be immunotoxicity, including toxic chemical depression of the bone marrow; some toxic effects in Cyp1a1(Ϫ/Ϫ) mice were noted at a BaP dose as low as 1.25 mg/kg/day. DNA post-labeling studies demonstrated dramatically higher BaP-DNA adduct levels in all Cyp1a1(Ϫ/Ϫ) tissues assayed, with the exception of the small intestine, which is probably a major site of BaP metabolism in Cyp1a1(ϩ/ϩ) mice. Different BaP-DNA adduct patterns were also observed between the two genotypes receiving oral BaP. Despite previous studies in vitro and in cell culture that have shown a participatory role for CYP1A1 in BaP toxicity, the present data indicate that, in the intact animal, inducible CYP1A1 is extremely important in detoxication and protection against oral BaP toxicity.

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Cellular localization of hepatic cytochrome 1B1 expression and its regulation by aromatic hydrocarbons and inflammatory cytokines

Cited by 47 publications

References 38 publications

Cytochrome P450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver

Cytochrome P450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver

Evaluation of the precision-cut liver and lung slice systems for the study of induction of CYP1, epoxide hydrolase and glutathione S-transferase activities

Oral Exposure to Benzo[a]pyrene in the Mouse: Detoxication by Inducible Cytochrome P450 Is More Important Than Metabolic Activation

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