Metabolism of benzo[a]pyrene in primary cultures of human hepatocytes: dose-response over a four-log range.

Abstract:

:Cultures of isolated human hepatocytes from three different human liver specimens were exposed for 24 h to media containing [3H]benzo[a]pyrene (BP) (0.1, 1.0, 10, 100 microM). The cells and media were harvested and extracted. Subsequent incubations of the aqueous phase with beta-glucuronidase and aryl sulfatase, followed by acetone/ethyl acetate extraction, were utilized to determine specific conjugation. Separation of the BP and its metabolites in the residues of the extracts was achieved by h.p.l.c. The capacity of human hepatocytes to metabolize BP was not saturated at up to 100 microM of BP, and the predominant metabolites produced were eluted in the void volume and were a mixture of highly polar BP forms. The next four most prevalent forms of BP metabolites were the 3-hydroxy BP, BP-4,5-dihydrodiol, BP-9,10-dihydrodiol, and BP-7,8-dihydrodiol. These metabolites all increased nearly linearly with dose. Conjugation varied for each different case, ranging from 31 to 91%, but a general trend clearly appeared; if beta-glucuronidation decreased, then sulfation increased and vice versa. BP metabolite binding to DNA was associated with the amount of unconjugated BP-7,8-dihydrodiol metabolite. BP metabolite binding to DNA was nearly linear from 0.1 to 10 microM BP; however, binding to DNA at 100 microM increased 64- to 844-fold over the binding occurring at 10 microM. Thus, human hepatocytes have a strong tendency to form highly polar BP metabolites, and total binding of BP to DNA over a four-log dose range is much less at 0.1-10 microM than one would predict from extrapolation from the high concentration (100 microM).

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Monteith DK,Novotny A,Michalopoulos G,Strom SC

doi

10.1093/carcin/8.7.983

subject

Has Abstract

pub_date

1987-07-01 00:00:00

pages

983-8

issue

7

eissn

0143-3334

issn

1460-2180

journal_volume

8

pub_type

杂志文章
  • CYP1A1 Ile462Val and MPO G-463A interact to increase risk of adenocarcinoma but not squamous cell carcinoma of the lung.

    abstract::Common polymorphisms in genes encoding phase I and phase II enzymes are considered to modify lung cancer risk due to changes in enzyme activity. Candidates include genetic variants of glutathione S-transferases (GSTM1, GSTT1 and GSTP1) and myeloperoxidase (MPO). We performed a large case-control study of these candida...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgi227

    authors: Larsen JE,Colosimo ML,Yang IA,Bowman R,Zimmerman PV,Fong KM

    更新日期:2006-03-01 00:00:00

  • Comparison of DNA alkali-labile sites induced by 4-(methylnitrosamino)-1(3-pyridyl)-1-butanone and 4-oxo-4-(3-pyridyl)butanal in rat hepatocytes.

    abstract::4-Oxo-4-(3-pyridyl)butanal (OPB) is an aldehyde formed during the activation of the tobacco-specific N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Using the DNA alkaline elution technique, the properties of DNA alkali-labile sites induced in the isolated rat hepatocytes by NNK and OPB were compar...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/12.11.2135

    authors: Demkowicz-Dobrzanski K,Castonguay A

    更新日期:1991-11-01 00:00:00

  • Tobacco smoke induces CYP1B1 in the aerodigestive tract.

    abstract::Several members of the P450 family, including cytochrome P450 1B1 (CYP1B1), can convert tobacco smoke (TS) procarcinogens, including benzo[a]pyrene (B[a]P), to carcinogenic intermediates. In this study we investigated the effects of TS condensate and B[a]P on the expression of CYP1B1 in vitro and in vivo. CYP1B1 mRNA ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgh243

    authors: Port JL,Yamaguchi K,Du B,De Lorenzo M,Chang M,Heerdt PM,Kopelovich L,Marcus CB,Altorki NK,Subbaramaiah K,Dannenberg AJ

    更新日期:2004-11-01 00:00:00

  • Correlation between the DNA damage in urinary bladder epithelium and the urinary 2-phenyl-1,4-benzoquinone levels from F344 rats fed sodium o-phenylphenate in the diet.

    abstract::The relationship between urinary metabolites and DNA damage in the urinary bladder epithelium of male and female rats was tested by alkaline elution assay after an intravesical injection of OPP or its urinary metabolites. 2-Phenyl-1,4-benzoquinone (PBQ) revealed a weak DNA-damaging activity in both sexes at 0.05-0.1%....

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/10.10.1823

    authors: Morimoto K,Sato M,Fukuoka M,Hasegawa R,Takahashi T,Tsuchiya T,Tanaka A,Takahashi A,Hayashi Y

    更新日期:1989-10-01 00:00:00

  • TMPRSS4 induces invasion and epithelial-mesenchymal transition through upregulation of integrin alpha5 and its signaling pathways.

    abstract::TMPRSS4 is a novel type II transmembrane serine protease that is highly expressed on the cell surface in pancreatic, thyroid and other cancer tissues, although its oncogenic significance and molecular mechanisms are unknown. Previously, we have shown that TMPRSS4 promotes invasion, migration and metastasis of human tu...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgq024

    authors: Kim S,Kang HY,Nam EH,Choi MS,Zhao XF,Hong CS,Lee JW,Lee JH,Park YK

    更新日期:2010-04-01 00:00:00

  • Transformation of immortalized woodchuck hepatic cell lines with the c-Ha-ras proto-oncogene.

    abstract::Woodchuck hepatocytes were immortalized with the simian virus 40 T antigen (SV40 T-ag) oncogene and utilized in an oncogenic transformation assay. Transfection of these cell lines with an activated C-Ha-ras oncogene (EJ6.6) resulted in the transformation of cells to a phenotype characterized by anchorage-independent g...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/17.4.631

    authors: Jacob JR,Tennant BC

    更新日期:1996-04-01 00:00:00

  • Effects of green tea catechins in a rat multi-organ carcinogenesis model.

    abstract::The effects of dietary administration of green tea catechins (GTC) were examined using a multi-organ carcinogenesis model. Groups of 15 F344 male rats were initially treated with a single i.p. administration of 100 mg/kg body wt N-diethyl-nitrosamine, 4 i.p. administrations of 20 mg/kg body wt N-methylnitrosourea, 4 s...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/14.8.1549

    authors: Hirose M,Hoshiya T,Akagi K,Takahashi S,Hara Y,Ito N

    更新日期:1993-08-01 00:00:00

  • Inhibition of intercellular communication in human keratinocytes by fractionated asphalt fume condensates.

    abstract::Asphalt fume condensate (AFC) and chromatographically separated fractions have been shown to cause cancer in mouse skin. The levels of known carcinogenic initiators in these complex mixtures, however, are considered too low to account for their carcinogenic potency. It has been proposed that AFC may contain co-carcino...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/13.6.1047

    authors: Wey HE,Breitenstein MJ,Toraason MA

    更新日期:1992-06-01 00:00:00

  • Insulin-like growth factor-binding protein-3 promotes transforming growth factor-{beta}1-mediated epithelial-to-mesenchymal transition and motility in transformed human esophageal cells.

    abstract::Insulin-like growth factor-binding protein (IGFBP)-3 is overexpressed frequently in esophageal squamous cell carcinoma. Yet, the role of IGFBP3 in esophageal tumor biology remains to be elucidated. We find that IGFBP3 facilitates transforming growth factor (TGF)-beta1-mediated epithelial-to-mesenchymal transition (EMT...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgq108

    authors: Natsuizaka M,Ohashi S,Wong GS,Ahmadi A,Kalman RA,Budo D,Klein-Szanto AJ,Herlyn M,Diehl JA,Nakagawa H

    更新日期:2010-08-01 00:00:00

  • Effect of modifying agents on the phenotypic expression of cytochrome P-450, glutathione S-transferase molecular forms, microsomal epoxide hydrolase, glucose-6-phosphate dehydrogenase and gamma-glutamyltranspeptidase in rat liver preneoplastic lesions.

    abstract::The expression of A and P forms of glutathione S-transferase (GST-A and P), two cytochrome P-450 isoenzymes (P-450 PB3a and P-450 MC2), microsomal epoxide hydrolase (mEHb), glucose-6-phosphate dehydrogenase (G6PD) and gamma-glutamyltranspeptidase (gamma-GT) was compared in preneoplastic liver lesions and background pa...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/9.4.547

    authors: Tsuda H,Moore MA,Asamoto M,Inoue T,Ito N,Satoh K,Ichihara A,Nakamura T,Amelizad Z,Oesch F

    更新日期:1988-04-01 00:00:00

  • Use of a mathematical model of rodent in vitro benzene metabolism to predict human in vitro metabolism data.

    abstract::Benzene, a ubiquitous environmental pollutant, is known to cause leukemia and aplastic anemia in humans and hematotoxicity and myelotoxicity in rodents. Toxicity is thought to be exerted through oxidative metabolites formed in the liver, primarily via pathways mediated by cytochrome P450 2E1 (CYP2E1). Phenol, hydroqui...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/20.8.1511

    authors: Lovern MR,Maris ME,Schlosser PM

    更新日期:1999-08-01 00:00:00

  • Metabolic cooperation in SK-HEP-1 human hepatoma cells following treatment with benzodiazepine tranquilizers.

    abstract::The ability of three benzodiazepine tranquilizers, diazepam, oxazepam and chlordiazepoxide chlorhydrate to block metabolic cooperation between human hepatoma cells was analysed using autoradiographical monitoring. Independent tests were performed with compound concentrations varying from 1 to 50 micrograms/ml. The res...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/8.7.1013

    authors: Rolin-Limbosch S,Moens W,Szpirer C

    更新日期:1987-07-01 00:00:00

  • Fisetin inhibits various attributes of angiogenesis in vitro and in vivo--implications for angioprevention.

    abstract::Studies have shown that fisetin, a small phytochemical molecule, has antitumor activity; however, its antiangiogenic activity has not yet been examined. Accordingly, herein, we investigated the antiangiogenic efficacy and associated mechanisms of fisetin in human umbilical vein endothelial cells (HUVECs). Fisetin (10-...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgr282

    authors: Bhat TA,Nambiar D,Pal A,Agarwal R,Singh RP

    更新日期:2012-02-01 00:00:00

  • Sulfotransferase 1A1 haplotypes associated with oral squamous cell carcinoma susceptibility in male Taiwanese.

    abstract::We have previously demonstrated that betel quid containing safrole induced DNA adducts are highly associated with the development of oral squamous cell carcinoma (OSCC) in Taiwan. Sulfotransferase (SULT) is essential for the formation of these adducts. To elucidate the effects of SULT1A1 haplotypes on OSCC susceptibil...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgn283

    authors: Chung YT,Hsieh LL,Chen IH,Liao CT,Liou SH,Chi CW,Ueng YF,Liu TY

    更新日期:2009-02-01 00:00:00

  • Dibenz[a,h]anthracene-induced subcutaneous tumors in mice. Strain sensitivity and the role of carcinogen metabolism.

    abstract::Four inbred strains of mice (C3H/HeJ, C57BL/6J, AKR/J, and DBA/2J) were injected s.c. with 150 micrograms of dibenz[a,h]anthracene and followed for 9 months. Strains C3H/HeJ and C57BL/6J were most susceptible to dibenz[a,h]anthracene-induced carcinogenesis with 80% and 53% incidence of tumors, respectively. Strains AK...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/4.5.513

    authors: Lubet RA,Connolly GM,Nebert DW,Kouri RE

    更新日期:1983-01-01 00:00:00

  • High-risk HPV16E6 stimulates hADA3 degradation by enhancing its SUMOylation.

    abstract::Despite significant research, our understanding of the molecular mechanisms of Human Papilloma Virus (HPV) induced cancers remains incomplete. Majority of invasive cervical cancers are caused by high-risk HPV 16 and 18. Two potent HPV oncoproteins, E6 and E7, promote human malignancies by disrupting the activities of ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgu104

    authors: Chand V,John R,Jaiswal N,Johar SS,Nag A

    更新日期:2014-08-01 00:00:00

  • E6AP goes viral: the role of E6AP in viral- and non-viral-related cancers.

    abstract::Since its discovery, the E3 ubiquitin ligase E6-associated protein (E6AP) has been studied extensively in two pathological contexts: infection by the human papillomavirus (HPV), and the neurodevelopmental disorder, Angelman syndrome. Vital biological links between E6AP and other viruses, namely hepatitis C virus and e...

    journal_title:Carcinogenesis

    pub_type: 杂志文章,评审

    doi:10.1093/carcin/bgz072

    authors: Bandilovska I,Keam SP,Gamell C,Machicado C,Haupt S,Haupt Y

    更新日期:2019-07-06 00:00:00

  • Association of chromosome 12p genetic polymorphisms with lung adenocarcinoma risk and prognosis.

    abstract::The mapping near Kras2 of pulmonary adenoma susceptibility 1 (Pas1), a major locus affecting inherited predisposition to lung cancer in mice prompted us to test the homologous human region (12p12) for association with lung adenocarcinoma, by a population-based study. We genotyped 213 lung adenocarcinoma patients and 2...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/18.10.1917

    authors: Manenti G,De Gregorio L,Pilotti S,Falvella FS,Incarbone M,Ravagnani F,Pierotti MA,Dragani TA

    更新日期:1997-10-01 00:00:00

  • Distribution of u.v.-induced repair events in higher-order chromatin loops in human and hamster fibroblasts.

    abstract::The repair of u.v.-induced damage in human and rodent cells was investigated at the level of DNA loops attached to the nuclear matrix. After 2 h post-u.v. incubation, DNase I digestion studies revealed a 3- to 4-fold enrichment of repair-labeled DNA at the nuclear matrix in four xeroderma pigmentosum cell strains belo...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/7.6.995

    authors: Mullenders LH,van Kesteren AC,Bussmann CJ,van Zeeland AA,Natarajan AT

    更新日期:1986-06-01 00:00:00

  • Sodium arsenite administration via drinking water increases genome-wide and Ha-ras DNA hypomethylation in methyl-deficient C57BL/6J mice.

    abstract::Arsenic is an established human carcinogen. Deficiencies in available animal models have inhibited a detailed analysis of the mechanism of arsenic induced cancer. This study sought to determine the role of a methyl-deficient diet in combination with sodium arsenite on the genomic methylation status and Ha-ras methylat...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/23.5.777

    authors: Okoji RS,Yu RC,Maronpot RR,Froines JR

    更新日期:2002-05-01 00:00:00

  • Reduced DNA-dependent protein kinase activity is associated with lung cancer.

    abstract::Reduced DNA repair capacity of carcinogen-induced DNA damage is now thought to significantly influence inherent susceptibility to lung cancer. DNA-dependent protein kinase (DNA-PK) is a serine-threonine kinase activated by the presence of double-strand breaks in DNA that appears to play a major role in non-homologous ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/22.5.723

    authors: Auckley DH,Crowell RE,Heaphy ER,Stidley CA,Lechner JF,Gilliland FD,Belinsky SA

    更新日期:2001-05-01 00:00:00

  • Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells.

    abstract::Many chemoradiation therapies cause DNA damage through oxidative stress. An important cellular mechanism that protects cells against oxidative stress involves DNA repair. One of the primary DNA repair mechanisms for oxidative DNA damage is base excision repair (BER). BER involves the tightly coordinated function of fo...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgm072

    authors: Zhang H,Mizumachi T,Carcel-Trullols J,Li L,Naito A,Spencer HJ,Spring PM,Smoller BR,Watson AJ,Margison GP,Higuchi M,Fan CY

    更新日期:2007-08-01 00:00:00

  • Sodium bisulfite induces morphological transformation of cultured Syrian hamster embryo cells but lacks the ability to induce detectable gene mutations, chromosome mutations or DNA damage.

    abstract::The ability of sodium bisulfite to induce morphological transformation and mutagenesis of cultured Syrian hamster embryo cells was examined. Treatment of the cells at neutral pH for 15 min with 5-20 mM sodium bisulfite resulted in a dose-dependent increase in cell transformation but no induction of gene mutations meas...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/11.10.1869

    authors: Tsutsui T,Barrett JC

    更新日期:1990-10-01 00:00:00

  • Microtubule disruption induced by estradiol in estrogen receptor-positive and -negative human breast cancer cell lines.

    abstract::Effects of estrogens on the cytoplasmic microtubule network were examined by the indirect immunofluorescence method using anti-beta-tubulin antibody. Estradiol, a naturally occurring estrogen, decreased the amount of cytoplasmic microtubule fibers during interphase in the human breast cancer cell lines MCF-7 and MDA-M...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/15.9.1875

    authors: Aizu-Yokota E,Ichinoseki K,Sato Y

    更新日期:1994-09-01 00:00:00

  • A comparative examination of the in vitro metabolism of five cyclopenta[a]phenanthrenes of varying carcinogenic potential.

    abstract::Metabolites of 15,16-dihydrocyclopenta[a]phenanthren-17-one and its 1- and 12-methyl homologues (all non-carcinogens) along with those from the 11-methyl and 11,12-dimethyl-17-ketones (carcinogens), produced in vitro by hepatic microsomes from methylcholanthrene induced rats, were separated by reverse phase h.p.l.c. I...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/6.8.1217

    authors: Coombs MM,Russell JC,Jones JR,Ribeiro O

    更新日期:1985-08-01 00:00:00

  • Pancreatic cancer cells express 25-hydroxyvitamin D-1 alpha-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3.

    abstract::The steroid hormone 1,25-dihydroxyvitamin D(3), [1,25(OH)(2)D(3), calcitriol], the active metabolite of vitamin D, exerts pleiotropic antitumor effects against several malignancies. However, the clinical use of this hormone is limited by hypercalcemia. 25-Hydroxyvitamin D(3), the prohormone of 1,25(OH)(2)D(3), is hydr...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgh086

    authors: Schwartz GG,Eads D,Rao A,Cramer SD,Willingham MC,Chen TC,Jamieson DP,Wang L,Burnstein KL,Holick MF,Koumenis C

    更新日期:2004-06-01 00:00:00

  • CYP1A2 is not the primary enzyme responsible for 4-aminobiphenyl-induced hepatocarcinogenesis in mice.

    abstract::4-Aminobiphenyl (4-ABP), a potent carcinogen in rodents (liver cancer) and human (bladder cancer), is found as an environmental contaminant and in tobacco smoke. Hemoglobin adducts and lung DNA adducts of 4-ABP are found in tobacco smokers. In vitro metabolism studies with human and rat liver microsomes have shown tha...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/20.9.1825

    authors: Kimura S,Kawabe M,Ward JM,Morishima H,Kadlubar FF,Hammons GJ,Fernandez-Salguero P,Gonzalez FJ

    更新日期:1999-09-01 00:00:00

  • Evidence for endogenous formation of tobacco-specific nitrosamines in rats treated with tobacco alkaloids and sodium nitrite.

    abstract::Carcinogenic tobacco-specific nitrosamines are present in tobacco products and are believed to play a significant role in human cancers associated with tobacco use. Additional amounts of tobacco-specific nitrosamines could be formed endogenously. We tested this hypothesis by treating rats with nicotine and sodium nitr...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/18.3.587

    authors: Carmella SG,Borukhova A,Desai D,Hecht SS

    更新日期:1997-03-01 00:00:00

  • Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects.

    abstract::Gene-environment interactions play an important role in folate metabolism, with a potential impact on human health. Deficiencies in the uptake of key micronutrients and variant genotypes can affect the folic acid cycle, modulating methyl group transfer in key processes and leading to increased cancer risk and Down syn...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgg064

    authors: Zijno A,Andreoli C,Leopardi P,Marcon F,Rossi S,Caiola S,Verdina A,Galati R,Cafolla A,Crebelli R

    更新日期:2003-06-01 00:00:00

  • Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma.

    abstract::In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that se...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgt030

    authors: Hyland PL,Freedman ND,Hu N,Tang ZZ,Wang L,Wang C,Ding T,Fan JH,Qiao YL,Golozar A,Wheeler W,Yu K,Yuenger J,Burdett L,Chanock SJ,Dawsey SM,Tucker MA,Goldstein AM,Abnet CC,Taylor PR

    更新日期:2013-05-01 00:00:00