Bromine adds across the enol ether moiety of 3a,8a-dihydrofuro[2,3-b]benzofuran and aflatoxin B1 to produce exclusively trans-dibromides, whereas addition of chlorine results in a mixture of trans- and cis-dichlorides. The resultant dibromides undergo nucleophilic substitution at C-2 or C-8, respectively, with retention of configuration, but the analogous substitution on the dichlorides is not so stereospecific. Peroxoacid oxidation of 3a,8a-dihydrofuro[2,3-b]benzofuran results in the addition of the peroxoacid across the terminal furan double bond via an epoxide or a resonance-stabilised carbonium ion intermediate to give cis- and trans-2-(3-chlorobenzoyloxy)-3-hydroxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran and trans-8-(3-chlorobenzoyloxy)-9-hydroxy-8,9-dihydroaflatoxin B1. The cis-2-(3-chlorobenzoyloxy)-3-hydroxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran ester rearranges in the reaction conditions to give trans-3-(3-chlorobenzoyloxy)-2-hydroxy-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran. When ethanol is added to the epoxidising system it acts as a competing nucleophile to give cis- and trans- hydroxy-acetals.
Abstract Human papillomavirus (HPV) DNA encoding the oncogenic proteins E6 and E7 is usually retained in cervical carcinomas, implicating these proteins as potential target antigens for immune recognition in this virally associated tumor. We have characterized endogenously processed peptides eluted from major histocompatibility complex class I molecules in cells infected with a recombinant vaccinia expressing the HPV‐16 E6 oncoprotein. The reverse‐phase chromatography profile of peptides eluted from isolated HLA‐A0201 molecules in cells expressing the E6 oncoprotein differs from that of cells not expressing E6. Sequential Edman degradation of novel peaks found in the peptide profiles from cells expressing HPV‐16 E6 led to the identification of a naturally processed HLA‐A0201‐restricted E6 peptide of sequence KLPQLCTEL. This approach has allowed the identification of a viral peptide which is processed and presented by cells expressing the E6 oncoprotein and is a likely target for cytotoxic T lymphocyte recognition in HLA‐A0201‐positive patients.
This chapter contains section titled: Herpesviridae Retroviridae Paramyxoviridae Avipox viruses Orthomyxoviridae Picornaviridae Parvoviridae Analgesics Togaviridae and Flaviridae (the arboviruses) Rhabdoviridae Circoviridae Papovaviridae Adenoviridae Coronaviridae Reoviridae Other diseases that may well be viral in origin
The patterns of expression of glutathione S-transferases A1 and A2 in human liver (hGSTA1 and hGSTA2, respectively) are highly variable, notably in the ratio of hGSTA1/hGSTA2. We investigated if this variation had a genetic basis by sequencing the proximal promoters (−721 to -1 nucleotides) of hGSTA1 and hGSTA2, using 55 samples of human liver that exemplified the variability of hGSTA1 and hGSTA2 expression. Variants were found in the hGSTA1 gene: -631T or G, -567T, -69C, -52G, designated as hGSTA1 *A; and -631G, -567G, -69T, -52A, designated as hGSTA1 *B. Genotyping for the substitution -69C > T by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), showed that the polymorphism was widespread in Caucasians, African–Americans and Hispanics, and that it appeared to conform to allelic variation. Constructs consisting of the proximal promoters of hGSTA1 *A, hGSTA1*B or hGSTA2, with luciferase as a reporter gene, showed differential expression when transfected into HepG2 cells:hGSTA1 *A ≈hGSTA2 >hGSTA1 *B. Similarly, mean levels of hGSTA1 protein expression in liver cytosols decreased significantly according to genotype:hGSTA1 *A > hGSTA1-heterozygous > hGSTA1*B. Conversely, mean hGSTA2 expression increased according to the same order of hGSTA1 genotype. Consequently, the ratio of GSTA1/GSTA2 was highly hGSTA1 allele-specific. Because the polymorphism in hGSTA1 correlates with hGSTA1 and hGSTA2 expression in liver, and hGSTA1-1 and hGSTA2-2 exhibit differential catalysis of the detoxification of carcinogen metabolites and chemotherapeutics, the polymorphism is expected to be of significance for individual risk of cancer or individual response to chemotherapeutic agents.
4,5-Epoxy-4,5-dihydro-1-nitropyrene (1-nitropyrene 4,5-oxide) and 9,10-epoxy-9,10-dihydro-1-nitropyrene (1-nitro-pyrene 9,10-oxide), which are electrophilic metabolites formed during the metabolism of the environmental pollutant, 1-nitropyrene, reacted slowly with glutathione. The rate of conjugation was greatly enhanced by the addition of purified rat liver glutathione (GSH) transferases, with transferases 3-3 and 4-4 exhibiting higher catalytic activities than transferases 1-1, 2-2 and 7-7. Two GSH conjugates were formed from each of the oxides: 1-nitropyrene 4,5-oxide gave a 1:1 mixture of 4-(glutathion-S-yl)-5-hydroxy-4,5-dihydro-1-nitro-pyrene and 5-(glutathion-S-yl)-4-hydroxy-4,5-dihydro-1-nitro-pyrene while 1-nitropyrene 9,10-oxide gave a 2:1 mixture of 9-(glutathlon-S-yl)-10-hydroxy-9, 10-dihydro-1-nitropyrene and 10-(glutathion-S-yl)-9-hydroxy-9,10-dihydro-1-nitro- pyrene. Both K-region oxides were converted to trans -di-hydrodiols by hepatic microsomal epoxide hydrase, and faster rates were observed with 1-nitropyrene 4,5-oxide. In subsequent experiments [4,5,9,10- 3 H]1-nitropyrene was administered to Sprague-Dawley rats by intravenous and intraperitoneal injections. HPLC analysis of biliary metabolites indicated the presence of four GSH conjugates that were identical to those obtained from reactions of the K-region oxides with GSH. In addition, glucuronide conjugates were detected from trans -4,5-dihydroxy-4,5-dihydro-1-nitropyrene (1-nitropyrene trans -4,5-dihydrodiol) but not trans -9,10-di-hydroxy-9,10-dihydro-1-nitropyrene (1-nitropyrene trans 9,10-dihydrodiol). These data combined with earlier studies indicate that 1-nitropyrene is oxidized preferentially to 1-nitropyrene 4,5-oxide and that, while the main detoxification pathway of 1-nitropyrene 9,10-oxide is GSH conjugation, 1-nitropyrene 4,5-oxide is excreted via both GSH conjugation and dihydrodlol formation followed by O -glucuronidation.
The kinetics and equilibria of S ‐nitrosothiol‐thiol (SNO—SH) exchange reactions were determined using differential optical absorption. At pH 7.4 and 37°C, k 2 values ranged from 0.9 M −1 · s −1 for the reaction between S ‐nitroso‐glutathione (GSNO) and N ‐acetyl‐penicillamine, and up to 279 M −1 · s −1 for the exchange between S ‐nitroso‐penicillamine (penSNO) and GSH. SNO—SH exchange involving GSH/GSNO and cysteine/cySNO was relatively rapid, k 2 approx. 80 M −1 · s −1 with an equilibrium constant slightly in favour of GSNO. GSNO was strongly favoured in equilibrium with penSNO, k eq 0.0039. In the case of SNO—SH exchange between S ‐nitroso human serum albumin (albSNO) and GSH or cysteine k 2 values were 3.2 and 9.1 M −1 · s −1 , respectively. The results show that the initial rate of SNO—SH exchange between physiological albSNO (7 μM) and venous plasma levels of GSH and cysteine is very slow, < 1%/min. On the other hand, if a nitrosothiol such as cySNO were to enter a cell, it would be rapidly converted to GSNO (43%/s).
Pilsbryna is revised based on new material collected during recent surveys of wet leaf-litter microhabitats in the southern Appalachian Mountains. Five species are recognized including Pilsbryna aurea Baker, 1929, P castanea Baker, 1931, P. no-dopalma new species and P. quadrilamellata new species. All species are redescribed or described. Pilsbryna vanattai (Walker and Pilsbry, 1902) is transferred to Pilsbryna from Glyphyalinia (Glyphyalus) based on genital and juvenile shell anatomy. Pilsbryna tridens Morrison, 1935, is reexamined based on newly available material; its placement in the genus Helicodiscus sensu lato is supported by new radular evidence. Pilsbryna species share unique genital and shell characteristics that are included in a redescription of the genus. The new generic definition combined with habitat information for all Pilsbryna species allows a better understanding of the geographic and microhabitat distribution of the genus.
Using the Pupilla faunas of Europe, North America, the Altai region of central Asia and eastern Asia, we consider whether the existing taxonomy based primarily on shell apertural characteristics correlates with relationships established on the basis of mitochondrial and nuclear DNA-sequence data. We obtained DNA sequence from nuclear ITS1 and ITS2 and mitochondrial COI and CytB from 80 specimens across 22 putative Pupilla taxa. The sequence data were analysed using maximum likelihood, maximum parsimony, Bayesian and neighbour-joining phylogenetic tree reconstruction, as well as base-pair substitution and insertion-deletion analysis. Revised species-level concepts were generated by identifying reciprocally monophyletic clades that exhibited unique conchological features. These analyses document that, although many previously described taxa have biological merit, the highly plastic nature of shell apertural features makes them unreliable indicators of species identity in several independent lineages. However, shell surface sculpture and architecture appear to provide more reliable diagnoses. Because of the traditional reliance of species-level taxonomy in Pupilla on plastic apertural features, too many species-level entities have been described in Europe and the Altai. Also, because taxonomically useful shell sculpture features have tended to be ignored, too few species have been described in eastern Asia and North America. As a result, confusion exists about species ranges, ecological tolerances and interpretation of Quaternary fossils within the genus. Based on these analyses three new species are described: P. alaskensis, P. hudsonianum and P. hokkaidoensis.
Abstract The glutathione S‐transferases (GSTs) catalyze the GSH‐dependent detoxification of reactive electrophiles such as genotoxic chemical carcinogens and cytotoxic chemotherapeutic agents. Allelic polymorphism in the GSTs has been used to investigate the hypothesis that GSTs are involved in susceptibility to human cancers. Such studies have resulted in low penetrance, high prevalence associations between cancer risk and GST polymorphisms. By examination of interindividual variation of GST expression it becomes clear that GST genotype alone is not an accurate predictor of GST expression. GST expression is tissue specific and interindividual variation of expression is at least 7‐fold in normal tissues. Thus, populations of the same genotype are actually heterogeneous as regards expression. Similarly, polymorphisms are not effective in all tissues and GST induction is not independent of genotype. Mechanistic models for chemical aspects of colorectal cancer and chemotherapy for breast cancer demonstrate some of the ways by which such interactions can be studied and the potential for future studies.
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