Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches

Abstract: This review summarizes the results found in studies investigating the enzymatic activation of two genotoxic nitro-aromatics, an environmental pollutant and carcinogen 3-nitrobenzanthrone (3-NBA) and a natural plant nephrotoxin and carcinogen aristolochic acid I (AAI), to reactive species forming covalent DNA adducts. Experimental and theoretical approaches determined the reasons why human NAD(P)H:quinone oxidoreductase (NQO1) and cytochromes P450 (CYP) 1A1 and 1A2 have the potential to reductively activate both nitro-aromatics. The results also contributed to the elucidation of the molecular mechanisms of these reactions. The contribution of conjugation enzymes such as N,O-acetyltransferases (NATs) and sulfotransferases (SULTs) to the activation of 3-NBA and AAI was also examined. The results indicated differences in the abilities of 3-NBA and AAI metabolites to be further activated by these conjugation enzymes. The formation of DNA adducts generated by both carcinogens during their reductive activation by the NOQ1 and CYP1A1/

Zur Modellierung von Rückversicherungsverträgen in der dynamischen Finanzanalyse

Zusammenfassung: Das Ziel dieser Arbeit besteht darin, verschiedene Rückversicherungsverträge in die dynamische Finanzanalyse zu integrieren und Auswirkungen auf Risiko und Rendite eines Schadenversicherers zu analysieren. Je nachdem, welchen Rückversicherungsvertrag und welche Intensität der Abhängigkeit wir dabei betrachten, finden wir sehr unterschiedliche Ergebnisse für Risikomaße wie die Ruinwahrscheinlichkeit oder das Expected Policyholder Deficit. Unser Untersuchungsergebnis hat eine hohe Relevanz für Regulierungsbehörden und Ratingagenturen, welche diese Maße als Fundament für die Aufsicht und für die Herleitung von Ratings nutzen. In unserer Arbeit erweitern wir die Ergebnisse aus Eling u. Toplek(2008) um eine detaillierte Analyse normaler Abhängigkeitsbeziehungen für verschiedene Rückversicherungsverträge und stellen diese Varianten im Rahmen einer neuen Beispielsimulation da

DETERMINAN PROPORSI DANA TABARRU’ PERUSAHAAN ASURANSI JIWA SYARIAH DI INDONESIA

Pengelolaan keuangan pada perusahaan asuransi jiwa syariah menggunakan sistem pemisahan dana (Islamic Split Fund Theory). Sistem pemisahan dana adalah memisahkan aset dan liabilitas kelompok dana tabarru’ dari kelompok dana perusahaan. Pemerintah belum mengatur masalah pembagian proporsi tabarru’ dan ujrah, oleh karenanya entitas asuransi jiwa syariah menentukan besaran proporsi tabarru’ dan ujrah dalam operasionalnya, sehingga terdapat perbedaan besaran proporsi pembagian tabarru’ dan ujrah antar perusahaan asuransi jiwa syariah. Tujuan penelitian ini adalah melakukan pengujian variabel determinan proporsi dana tabarru’ pada asuransi jiwa syariah. Metode penelitian yang digunakan dalam penelitian ini adalah metode kausalitas dengan pendekatan kuantitatif. Populasi pada penelitian ini adalah Perusahan Asuransi Jiwa Syariah yang terdaftar di Otoritas Jasa Keuangan (OJK). Metode purposive sampling digunakan untuk penentuan sampel penelitian ini, sampel yang digunakan sebanyak 11 perusahaan asuransi jiwa syariah. Teknik analisis statistik yang digunakan dalam penelitian ini adalah analisis regresi data panel. Variabel dependen dalam penelitian ini adalah proporsi dana tabarru’ dan variabel independen dalam penelitian ini tingkat klaim, kegiatan retakaful, dan beban usaha. Hasil penelitian menunjukkan bahwa kegiatan retakaful berpengaruh terhadap proporsi dana tabarru’ dengan arah positif, beban usaha berpengaruh negatif terhadap proporsi dana tabarru’. Di sisi lain, variabel klaim tidak memiliki pengaruh terhadap proporsi dana tabarru’.;--Financial management of the Sharia Life insurance company uses a system of funds separation (Islamic Split Fund Theory). The fund separation system is to separate the assets and liabilities of the Tabarru Fund group from the Company's Fund group. The government has not set the problem of distribution of Tabarru ' and Ujrah, therefore the Sharia life insurance entity determines the proportion of Tabarru ' and Ujrah in its operations, so that there is a difference in the proportion of distribution of tabarru ' and Among Sharia life insurance companies. The purpose of this research is to test variable determinant proportion of tabarru funds ' on Sharia life insurance. The research methods used in this study are causality methods with a quantitative approach. The population in this research is the Sharia life insurance company registered with the Financial Services Authority (OJK). The purposive sampling method is used for the sample determination of this research. The statistical analysis techniques used in this study were the analysis of the regression data panels. The dependent variables in this study are the proportion of tabarru funds ' and independent variables in the study of the level of claims, retakaful activities, and operating expenses. The results showed that the retakaful activity had an effect on the proportion of the Tabarru ' fund in a positive direction, the operating burden negatively impacted the proportion of the Tabarru ' fund. On the other hand, the claim variable has no influence on the proportion of the Tabarru fund '

Chemical and molecular basis of the carcinogenicity of Aristolochia plants

The herbal drug aristolochic acid (AA), which is derived from the Aristolochia species, has been associated with the development of a novel nephropathy, designated as aristolochic acid nephropathy (AAN), and with human urothelial cancer. The major components of the plant extract AA are nitrophenanthrene carboxylic acids, which, after metabolic activation, are genotoxic mutagens. The major activation pathway of AA involves reduction of the nitro group, primarily catalyzed by NAD(P) H: quinone oxidoreductase (NQO1), to an electrophilic cyclic N-acylnitrenium ion that reacts preferentially with purine bases to form covalent DNA adducts. These specific AA-DNA adducts have been identified and detected in experimental animals exposed to AA or botanical products containing AA, and in urothelial tissues from AAN patients. In rodent tumors induced by AA the predominantly formed DNA adduct 7-(deoxyadenosin-N-6-yl) aristolactam I has been associated with the activation of ras oncogenes through the characteristic transversion mutation AT -> TA. This mutation has been identified in the p53 gene of urothelial tumors of a patient with AAN (induced by use of a herbal product) and in several patients suffering from Balkan endemic nephropathy (BEN) with specific AA-DNA adducts. This is a rare example of a human cancer causally linked to a distinct environmental exposure (ie, use of a herbal product), where the carcinogenic process of initiation is well established, linking formation of carcinogen-specific exposure (specific DNA adduct formation) with the presence of characteristic human tumor mutations

The environmental pollutant and carcinogen 3-nitrobenzanthrone induces cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase in rat lung and kidney, thereby enhancing its own genotoxicity

3-Nitrobenzanthrone (3-NBA) is a carcinogen occurring in diesel exhaust and air pollution. Using the P-32-postlabelling method, we found that 3-NBA and its human metabolite, 3-aminobenzanthrone (3-ABA), are activated to species forming DNA adducts by cytosols and/or microsomes isolated from rat lung, the target organ for 3-NBA carcinogenicity, and kidney. Each compound generated identical five DNA adducts. We have demonstrated the importance of pulmonary and renal NAD(P)H:quinone oxidoreductase (NQO1) to reduce 3-NBA to species that are further activated by N,O-acetyltransferases and sulfotransferases. Cytochrome P450 (CYP) 1A1 is the essential enzyme for oxidative activation of 3-ABA in microsomes of both organs, while cyclooxygenase plays a minor role. 3-NBA was also investigated for its ability to induce NQO1 and CYP1A1 in lungs and kidneys, and for the influence of such induction on DNA adduct formation by 3-NBA and 3-ABA. When cytosols from rats treated i.p. with 40 mg/kg bw of 3-NBA were incubated with 3-NBA, DNA adduct formation was up to 2.1-fold higher than in incubations with cytosols from control animals. This increase corresponded to an increase in protein level and enzymatic activity of NQO1. Incubations of 3-ABA with microsomes of 3-NBA-treated rats led to up to a fivefold increase in DNA adduct formation relative to controls. The stimulation of DNA adduct formation correlated with the potential of 3-NBA to induce protein expression and activity of CYP1A1. These results demonstrate that 3-NBA is capable to induce NQO1 and CYP1A1 in lungs and kidney of rats thereby enhancing its own genotoxic and carcinogenic potential. (C) 2008 Elsevier Ireland Ltd. All rights reserved