Benzo[e]pyrene   中文名称: 苯并(E)芘

Metabolism / Metabolites
The 4,5-dihydrodiol is the major metabolite of benzo(e)pyrene, but the 9,10-dihydrodiol has also been detected as a minor product following incubation of benzo(e)pyrene with rat liver preparations. Glucuronic acid conjugates of 3-hydroxy-benzo(e)pyrene and of the 4,5-dihydrodiol have been reported in hamster embryo cells. The formation of the 4,5,9,10-tetraol and the 9,10,11,12-tetraol as well as unidentified phenols from the precursor 9,10-dihydrodiol have also been reported using hepatic microsomal preparations from various species including humans.
The potential biological activity of benzo(e)pyrene was investigated by a determination of the mutagenic activity of the polycyclic hydrocarbon and six of its derivatives in the absence and presence of a cytochrome P-450-dependent monooxygenase system. In the presence of hepatic microsomes from Aroclor 1254-pretreated rats or the cytochrome P-450-dependent monooxygenase system purified to near homogeneity from these microsomes, benzo(e)pyrene, trans-9,10-dihydroxy-9,10-dihydrobenzo(e)pyrene (bay region dihydrodiol), and trans-9,10-dihydroxy-9,10,11,12-tetrahydrobenzo(e)pyrene were metabolized to products which had little or no mutagenic activity toward strains TA 98 and TA 100 of Salmonella typhimurium. Under the same assay conditions, the products formed from trans-4,5-dihydroxy-4,5-dihydrobenzo(e)pyrene (K-region dihydrodiol) had modest mutagenic activity. In contrast with these results, 9,10-dihydrobenzo(e)pyrene was metabolically activated to potent mutagenic products which were 10- to 25-fold more active than the products formed from benzo(e)pyrene. The high intrinsic mutagenic activity of the chemically synthesized benzo ring tetrahydroepoxide of 9,10-dihydrobenzo(e)pyrene in both strains of bacteria and in cultured Chinese hamster V79 cells suggested that the high mutagenicity of 9,10-dihydrobenzo(e)pyrene after metabolism was mediated by this bay region tetrahydroepoxide. Liver microsomal metabolites of several of the benzo(e)pyrene derivatives were analyzed by high pressure liquid chromatography. Incubation of 9,10-dihydrobenzo(e)pyrene with hepatic microsomes from untreated or Aroclor 1254-pretreated rats confirmed the metabolic formation of the benzo ring epoxide of 9,10-dihydrobenzo(e)pyrene and established the formation of several other metabolites. In contrast to these results, trans-9,10-dihydroxy-9,10-dihydrobenzo(e)pyrene was not metabolized to benzo ring diol epoxides but rather was converted to 4,5,9,10-tetrahydroxy-4,5,9,10-tetrahydrobenzo(e)pyrene along with three phenolic derivatives of the dihydrodiol. Thus, lack of formation of a benzo ring epoxide provides a rationale for the inability of 9,10-dihydroxy-9,10-dihydrobenzo(e)pyrene to be metabolically activated by rat liver enzymes to mutagenic products and may contribute to the low carcinogenic activity of benzo(e)pyrene in rodents.
The major organic solvent sol metabolite formed in extracellular medium after 24 hr of culture (hamster embryo cells) with B[e]P was K-region dihydrodiol 4,5-dihydro-4,5-dihydroxybenzo[e]pyrene and small amt monohydroxybenzo[e]pyrenes.
The genotoxicity of 15 polycyclic aromatic hydrocarbons was determined with the alkaline version of the comet assay employing V79 lung fibroblasts of the Chinese hamster as target cells. These cells lack the enzymes necessary to convert PAHs to DNA-binding metabolites. ... 11 PAHs, i.e., benzo[a]pyrene (BaP), benz[a]anthracene, 7,12-dimethylbenz[a]anthracene, 3-methylcholanthrene, fluoranthene, anthanthrene, 11H-benzo[b]fluorene, dibenz[a,h]anthracene, pyrene, benzo[ghi]perylene and benzo[e]pyrene caused DNA strand breaks even without external metabolic activation, while naphthalene, anthracene, phenanthrene and naphthacene were inactive. When the comet assay was performed in the dark or when yellow fluorescent lamps were used for illumination the DNA-damaging effect of the 11 PAHs disappeared. White fluorescent lamps exhibit emission maxima at 334.1, 365.0, 404.7, and 435.8 nm representing spectral lines of mercury. In the case of yellow fluorescent lamps these emissions were absent. Obviously, under standard laboratory illumination many PAHs are photo-activated, resulting in DNA-damaging species. This feature of PAHs should be taken into account when these compounds are employed for the initiation of skin cancer. ...
PAH metabolism occurs in all tissues, usually by cytochrome P-450 and its associated enzymes. PAHs are metabolized into reactive intermediates, which include epoxide intermediates, dihydrodiols, phenols, quinones, and their various combinations. The phenols, quinones, and dihydrodiols can all be conjugated to glucuronides and sulfate esters; the quinones also form glutathione conjugates. (L10)

Toxicity Summary
IDENTIFICATION AND USE: Benzo(e)pyrene (B(e)P) is a constituent of coal tar. It is used in experimental research. Polycyclic aromatic hydrocarbons are a group of chemicals that are formed during the incomplete burning of coal, oil, gas, wood, garbage, or other organic substances, such as tobacco and charbroiled meat. HUMAN EXPOSURE AND TOXICITY: B(e)P is a toxic element in cigarette smoke. It is a toxicant to human retinal pigment epithelial cells in vitro. It causes cell death and induces apoptosis by the involvement of multiple caspase pathways. Human microvascular endothelial cells exposed to B(e)P showed a decrease in cell viability. It induced unscheduled DNA synthesis in HeLa cells in the presence of an exogenous metabolic system. The agent is not classifiable as to its carcinogenicity to humans. ANIMAL STUDIES: It has been observed to cause violent uveitis when injected intraocularly in animal eyes. One study showed that B(e)P is a very weak tumor initiator, a weak complete carcinogen, a moderate tumor promoter, possibly a weak co-tumor-initiator when given with benzo(a)pyrene, and a potent anit-tumor-initiator when given with 7,12-dimethylbenz[a]anthracene. In another study, a group of 20 female mice received applications of a 0.1% solution of benzo(e)pyrene by skin painting for life. Of five animals that survived 13 months after the start of treatment, two had skin papillomas and three had carcinomas. In other experiment, 30 female mice received 100 ug benzo(e)pyrene by skin application for 30 weeks. At 30 weeks, 68% of the mice had papillomas (2.1 papillomas/mouse); and at 40 weeks, 24% of mice had carcinomas. Benzo(e)pyrene was mutagenic to Salmonella typhimurium in the presence of an exogenous metabolic system. It did not induce mitotic recombination in yeast. It did not induce mutations or sister chromatid exchange in cultured mammalian cells and was negative in assays for morphological transformation. In the one available report, it did not induce chromosomal aberrations in vitro. In the one available in-vivo study, it induced sister chromatid exchange, but not chromosomal aberrations in hamster bone marrow.
The ability of PAH's to bind to blood proteins such as albumin allows them to be transported throughout the body. Many PAH's induce the expression of cytochrome P450 enzymes, especially CYP1A1, CYP1A2, and CYP1B1, by binding to the aryl hydrocarbon receptor or glycine N-methyltransferase protein. These enzymes metabolize PAH's into their toxic intermediates. The reactive metabolites of PAHs (epoxide intermediates, dihydrodiols, phenols, quinones, and their various combinations) covalently bind to DNA and other cellular macromolecules, initiating mutagenesis and carcinogenesis. (L10, L23, A27, A32)

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Interactions
... In this research, we studied the photoirradiation of isomeric methylbenzo[a]pyrene (MBaP) and methylbenzo[e]pyrene (MBeP) by UVA light in the presence of a lipid, methyl linoleate, and evaluated the potential of these compounds to induce lipid peroxidation. The compounds chosen for study included BaP, 3-MBaP, 4-MBaP, 6-MBaP, 7-MBaP, 10-MBaP, BeP, 4-MBeP, and 9-MBeP. The results indicate that upon photoirradiation by UVA at 7 and 21 J/sq cm, these compounds induced lipid peroxidation. The levels of the induced lipid peroxidation were similar among BaP and the isomeric MBaPs, and among the BeP and MBePs, with the BaP group higher than the BeP group. There was also a co-relation between the UV A light dose and the level of lipid peroxidation induced. Lipid peroxide formation was inhibited by NaN3 (singlet oxygen and free radical scavenger) and was enhanced by the presence of deuterium oxide (D2O) (extends singlet oxygen lifetime). These results suggest that photoirradiation of MBaPs and MBePs by UVA light generates reactive oxygen species (ROS), which induce lipid peroxidation.
Benzo[e]pyrene (B[e]P) inhibited 7,12-dimethylbenz[a]anthracene (DMBA) skin tumor-initiation in mice by 84%, whereas pyrene and fluoranthene inhibited DMBA initiation by 50 and 34%, respectively. ...
Benzo(e)pyrene, when administered to mice by skin application together with 7,12-dimethylbenz(a)anthracene or benzo(a)pyrene, resulted in fewer skin tumors than with 7,12-dimethylbenz(a)anthracene alone and in more skin tumors than with benzo(a)pyrene alone.
Groups of 20 female Fischer 344 rats (aged unspecified) received implants of beeswax pellets containing either 1 mg benzo(a)pyrene, 0.5 mg benzo(a)pyrene, 1 mg benzo(e)pyrene (purity unspecified), 0.5 mg benzo(a)pyrene + 1 mg benzo(e)pyrene, or 1 mg benzo(a)pyrene + 1 mg benzo(e)pyrene in tracheas from isogenic donors transplanted subcutaneously in the retroscapular region (two tracheas/animal). All surviving animals were killed 28 months after the start of exposure. Benzo(e)pyrene did not induce tumors in tracheal explants, while 1 mg benzo(a)pyrene induced carcinomas in 65% of the grafts. Benzo(e)pyrene appeared to reduce the incidence of carcinomas from 65% (benzo(a)pyrene alone) to 40% (benzo(a)pyrene plus benzo(e)pyrene). However, the incidence of sarcoma in tracheal and peritracheal explants was enhanced two- to three-fold by benzo(e)pyrene given with benzo(a)pyrene compared with benzo(a)pyrene alone.
For more Interactions (Complete) data for BENZO(E)PYRENE (6 total), please visit the HSDB record page.

[1]. Fluorescence measurements of benzene, naphthalene, anthracene, pyrene, fluoranthene, and benzo(e)pyrene in water. Anal Chem. 1976 Mar;48(3):524-8.

Benzo[e]pyrene appears as colorless crystals or white crystalline solid. (NTP, 1992)
Benzo[e]pyrene is an ortho- and peri-fused polycyclic arene consisting of five fused benzene rings. It is listed as a Group 3 carcinogen by the IARC. It has a role as a mutagen and a carcinogenic agent.
Benzo[e]pyrene has been reported in Nicotiana tabacum with data available.
Benzo[e]pyrene is one of over 100 different polycyclic aromatic hydrocarbons (PAHs). PAHs are chemicals that are formed during the incomplete burning of organic substances, such as fossil fuels. They are usually found as a mixture containing two or more of these compounds. (L10)

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Mechanism of Action
... Previous studies from /the author's/ laboratory reported that benzo(a)pyrene (Bap) influenced efflux transport of rhodamine 123 (Rho-123) by induction of P-glycoprotein (P-gp) in Caco-2 cells. The present study investigated whether induction of P-gp and the enhanced efflux transport of Rho-123 were caused by benzo(e)pyrene (Bep), which has a structure similar to Bap, but is not a carcinogenic compound. In Caco-2 monolayer exposed to 50 uM Bep for 72 hr, the ratio of the apparent permeability coefficient (P(app)) of Rho-123 efflux increased significantly compared to that of the control monolayer. Similarly, a significant increase in expression of MDR1 mRNA and of P-gp at the protein level were detected by RT-PCR and by Western blot analysis, respectively, in Caco-2 cells exposed to Bep, compared to that of the control. Caco-2 cells exposed to Bep showed oxidative stress that was detected by fluorescence microscopy using aminophenyl fluorescein. However, the oxidative stress was weaker compared with that of Bap. The cellular GSH content was decreased to 80% or 59% of control cells, respectively, in Caco-2 cells exposed to either Bep or Bap. Our results further show that Bep or Bap-induced P-gp in Caco-2 cells might have been the result of oxidative stress rather than DNA damage.
The mechanism of the co-carcinogenic activity of benzo[e]pyrene (BeP) was investigated by determining the effects of benzo[e]pyrene on the binding of the carcinogen benzo[a]pyrene (BaP) to DNA in Sencar mouse epidermis. The dose of benzo[a]pyrene used was 20 nmol/mouse a dose which is not carcinogenic in a single application but is carcinogenic after multiple treatments such as those in the benzo[a]pyrene-benzo[e]pyrene co-carcinogenesis experiments described by Van Duuren and Goldschmidt. After 3 hr of exposure to [(3)H]benzo[a]pyrene and benzo[e]pyrene at benzo[a]pyrene:benzo[e]pyrene dose ratios of 1:3 and 1:10, [(3)H]benzo[a]pyrene-DNA adducts in both benzo[e]pyrene-treated groups were lower than in an acetone-benzo[a]pyrene control group. After 12 and 24 hr of exposure the benzo[a]pyrene-benzo[e]pyrene (1:10) group contained 19% and 33% higher [(3)H]benzo[a]pyrene-DNA adduct levels than the control. In the benzo[a]pyrene-benzo[e]pyrene 11:3) group the amount of [(3)H]benzo[a]pyrene-DNA adduct levels was higher than the control after 12 hr. Benzo[e]pyrene cotreatment with either [(3)H]benzo[a]pyrene-7 8-dihydrodiol or anti-[(3)H]benzo[a]pyrene had no effect on the amount of benzo[a]pyrene DE-DNA adducts present. These results demonstrate that the cocarcinogen benzo[e]pyrene increases the amount of a low dose of benzo[a]pyrene that binds to mouse epidermal DNA and indicate that the increase in benzo[a]pyrene-DNA adducts results from increased metabolism of benzo[a]pyrene to the proximate carcinogen benzo[a]pyrene-7 8-dihydrodiol.

C20H12

252.30900

252.093

192-97-2

9128

Prisms or plates from benzene
Pale yellow needles (from benzene or methanol)
Colorless crystals or white crystalline solid

1.3±0.1 g/cm3

467.5±12.0 °C at 760 mmHg

177-180ºC(lit.)

228.6±13.7 °C

0.0±0.6 mmHg at 25°C

1.887

6.4

0

0

0

0

20

336

0

C1=CC=C2C(=C1)C3=CC=CC4=C3C5=C(C=CC=C25)C=C4

TXVHTIQJNYSSKO-UHFFFAOYSA-N

InChI=1S/C20H12/c1-2-8-16-15(7-1)17-9-3-5-13-11-12-14-6-4-10-18(16)20(14)19(13)17/h1-12H

benzo[e]pyrene

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。