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In contrast to hepatocytes or hepatoma cells lines, it has been long proposed that drug-metabolizing enzymes are present at low or undetectable levels in liver progenitor cells. In this study, we determined expression and inducibility of CYP1A1, CYP1B1, AKR1A1and AKR1C9, which are involved in two alternative pathways of oxidative metabolism of PAHs, in rat liver epithelial WB-F344 cell line, an in vitro model of liver progenitor cells. We further measured DNA adduct formation and induction of reactive oxygen species ROS ; as two parameters of genotoxic insult, which may lead to apoptosis and phosphorylation of H2AX and p53 proteins. AKR1A1, although being present at significant levels, was not induced by PAHs. Several carcinogenic PAHs inducing high levels of CYP1A1 and CYP1B1, such as benzo[b]fluoranthene and dibenzo[a, h]anthracene, formed only a limited amount of DNA adducts. Additionally, despite their ability to induce AKR1C9, which may contribute to oxidative stress, no increase in ROS levels, p53 and H2AX phosphorylation and apoptosis was observed. In contrast, dibenzo[a, l]pyrene, benzo[a]pyrene and 7, 12-dimethylbenz[a]anthracene formed high levels of DNA adducts, induced arrest in S-phase of cell cycle and apoptosis. Simultaneously, all these potent genotoxins induced ROS production as well, suggesting that the AKRdependent pathway leading to oxidative DNA damage may contribute to their genotoxic effects. [This work was supported by the Czech Ministry of Agriculture, grant No. MZE0002716201.] and coreg.
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Enroll children under 18 or illiterate individuals. All study related materials including the informed consent forms will be available in English and Spanish as required by each study site. The informed consent process will give individuals all of the relevant information they need in order to decide whether to participate, or to continue participation, in this study. Potential research participants will be permitted to ask questions and to exchange information freely with the study investigators. Only listed study investigators may obtain informed consent from potential study participants. The investigators will keep research participants fully informed of any new information that could affect their willingness to continue study participation. 13.5. Participant Confidentiality Members of the study staff sites are all trained in patient confidentiality for their participation in the ATN. The only sites at which this study will be performed are both ATN Trials Units ATU ; . The log of study participant names and other protected health information will be kept in a double-locked area. All computer information about study volunteers will be kept on a computer with log-on passwords. Laboratory specimens are labeled with study numbers and date, and are delivered or shipped by study staff. The study sites' data management and clinical staff are the only personnel with access to the protected health information of study volunteers. Each member of the staff has log-on identification and password, logs off before leaving a computer screen unattended, and closes their office door when out of the office. All research records will be kept indefinitely following closure of this study. To further protect the privacy of the study participants, the ATN has obtained a Certificate of Confidentiality from the U.S. Department of Health and Human Services DHHS ; . With this Certificate in place, the ATN researchers cannot be forced to turn over identifying information about a study participant in any Federal, State, or local criminal, administrative, legislative, or other proceedings. This Certificate does not prevent a study participant from volunteering to turn over their research information nor does it prevent researchers from providing research-related information to others when requested by the study participant. 13.6. Special Populations This section outlines considerations made for the inclusion or exclusion of special populations in this study. 13.6.1 Pregnant Women Pregnancy is an exclusion criterion because there are no current recommendations for the use of 3% w w SPL7013 Gel during pregnancy. A urine pregnancy test will be performed on all women at all clinic visits, and positive tests will be noted on the Eligibility Criteria form. During the informed consent process, women will be informed that SPL7013 Gel is not known to prevent pregnancy and that the effect of SPL7013 Gel on a developing human fetus is unknown. All potential participants will be required by the Eligibility Criteria for Screening and Enrollment to be currently using a reliable MTN-004 Version 2.0 Page 73 15 May 2007 and losartan!
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