Maternal and infant touching behaviours during perturbed interactions: Associations with maternal depressive symptomatology and infant crying.

Touch is an important means through which mothers and infants co-regulate during periods of stress or perturbation. The present study examined the synchrony of maternal and infant touching behaviours among 41 mother-infant dyads, some of whom were deemed at-risk due to maternal depressive symptomatology. Mothers and their 4-month-old infants participated in the Still-Face (maternal emotional unavailability; SF) and Separation (maternal physical unavailability; SP) procedures. Infant crying was examined across procedures and investigated as a brief period of perturbation. Results revealed that mothers and infants displayed a positive pattern of tactile synchrony (coordinated, analogous changes in touch) during infant crying episodes. However, dyads in the high depression group displayed significantly less affectionate touch during instances of infant crying. Furthermore, more depressive symptoms were associated with less maternal and infant touch and lower rates of infant crying. This group of dyads may be less expressive via touch, be less affected by disruptions in their interactions, have impaired regulatory abilities, or simply require minimal amounts of touch to mutually regulate following social stressors and during brief perturbation periods. These findings enrich our limited knowledge about the dynamic interplay of maternal and infant touch and inform preventative intervention programs for at-risk groups.

Eliminating Leakage Errors in Hyperfine Qubits.

Population leakage outside the qubit subspace presents a particularly harmful source of error that cannot be handled by standard error correction methods. Using a trapped ^{171}Yb^{+} ion, we demonstrate an optical pumping scheme to suppress leakage errors in atomic hyperfine qubits. The selection rules and narrow linewidth of a quadrupole transition are used to selectively pump population out of leakage states and back into the qubit subspace. Each pumping cycle reduces the leakage population by a factor of ∼3, allowing for an exponential suppression in the number of cycles. We use interleaved randomized benchmarking on the qubit subspace to show that this pumping procedure has negligible side effects on the qubit subspace, bounding the induced qubit memory error by ≤2.0(8)×10^{-5} per cycle, and qubit population decay to ≤1.4(3)×10^{-7} per cycle. These results clear a major obstacle for implementations of quantum error correction and error mitigation protocols.

Predictors of depressive symptoms in primary caregivers of young children with or at risk for developmental delay.

BACKGROUND: Despite extensive research with families raising children with or at risk for developmental delay (DD), it is not clear whether primary caregivers of these children are at increased risk for depressive symptoms. Discrepant findings in the literature may be owing to heterogeneity of child problems. More research is needed on child, parent and family variables that may increase risk for, or resilience to, caregiver depressive symptoms. Some studies have found that parental resources (e.g. social support and coping strategies) may buffer the effects of parental distress, while other studies have highlighted the role of parental self-efficacy. METHODS: We examined Beck Depression Inventory (BDI) scores in 178 primary caregivers (mainly biological mothers) who had 2-year-old children with or at risk for DD owing to: (a) low birthweight, prematurity or multiple birth (n = 58), (b) other known reasons (e.g. Down syndrome, spina bifida) (n = 67), or (c) unknown reasons (n = 69). RESULTS: We found that 20% (n = 35) of the caregivers scored above the BDI clinical cut-off for depression. Analysis of variance revealed that caregivers with elevated BDI scores had higher child behaviour problem and escape-avoidance coping scores, and lower social support and parent self-efficacy, compared with caregivers without depressive symptoms. Caregivers with children who had DD for unknown reasons had higher BDI scores than caregivers of the other two groups of children. Regression analyses showed that child behaviour problems, escape-avoidance coping strategies and social support predicted caregiver BDI scores, but caregiver self-efficacy only did so when entered independently of social support. Only social support mediated and (marginally) moderated the relationship between child behaviour problems and caregiver depressive symptoms. CONCLUSIONS: These findings suggest that early intervention programmes should carefully consider the interaction of child characteristics (e.g. Diagnosis and behaviour problems), caregiver resources (e.g. coping strategies and social support), and parental mental health and mood when planning and tailoring services for families of children with or at risk for DD.

Optimizing the dose of intrathecal morphine in older patients undergoing hip arthroplasty.

UNLABELLED: Intrathecal (IT) morphine provides excellent postoperative analgesia but may result in many side effects, including postoperative nausea and vomiting, pruritus, and respiratory depression, particularly at larger doses. Older patients may be at particular risk. The optimal dose of spinal morphine in older patients undergoing hip arthroplasty is not known. We designed this prospective, randomized, controlled, double-blinded study to evaluate the analgesic efficacy and side effect profile of 50-200 microg of IT morphine in older patients undergoing elective hip arthroplasty. Sixty patients older than 65 years undergoing elective hip arthroplasty were enrolled. Patients were randomized to receive spinal anesthesia with 15 mg of bupivacaine and IT morphine in four groups: 1). 0 microg, 2). 50 microg, 3). 100 microg, and 4). 200 microg. IT morphine 100 and 200 microg produced effective pain relief and decreased the postoperative requirement for morphine compared with control. IT morphine 50 microg did not provide effective pain relief. Both 100 and 200 microg of IT morphine provided comparable levels of postoperative analgesia. There were no between-group differences in postoperative nausea and vomiting, sedation, respiratory depression, or urinary retention. Pruritus was significantly more frequent with 200 microg of IT morphine. In conclusion, 100 microg of IT morphine provided the best balance between analgesic efficacy and side effect profile in older patients undergoing hip arthroplasty. IMPLICATIONS: The dosage of intrathecal morphine that provides the best balance between analgesic efficacy and side effect profile in the older patient undergoing hip arthroplasty is not known. This prospective, randomized, controlled, double-blinded clinical trial demonstrates that a dose of 100 microg of intrathecal morphine provides the best balance between efficacy and side effects, compared with doses of 0, 50, and 200 microg of morphine, in this patient population.

Effects of feeding regimens on bodyweight, composition and condition score in cats following ovariohysterectomy.

The effects of ovariohysterectomy on bodyweight, composition and condition score were evaluated in 49 cats that were fed ad libitum and 11 cats that had their food allowances controlled with the aim of maintaining a stable bodyweight. In cats fed ad libitum, bodyweight increased by an average of 31 per cent in the 12 months following ovariohysterectomy compared with 3.1 per cent over the 12 months before surgery, and this was largely due to increased body fat content. There was no difference in weight gain between cats fed dry or canned foods, but weight gain was inversely related to age and bodyweight at the time of neutering. Mean bodyweight increased by 7.5 per cent in the controlled feeding group, compared with 3.6 per cent over the 12 months before surgery, and individual bodyweights were maintained to within 10 per cent of pre-neutering values in nine cats. The other two cats experienced substantial weight gain (+20 per cent and +36 per cent), despite being fed only 40 kcal/kg/day. There were no significant changes in body composition of cats with controlled dietary allowances and their condition scores were significantly lower than those of cats fed ad libitum. The results confirm a link between ovariohysterectomy and the development of obesity in cats with free access to food, and indicate that substantial reductions in energy intake are required to prevent weight gain in such cats.

Adverse effects of fetal cocaine exposure on neonatal auditory information processing.

BACKGROUND: Studies with animals have shown that in utero exposure to cocaine interferes with fetal brain development by disrupting the processes of neuronal proliferation, differentiation, and migration, often leading to subsequent neurobehavioral deficits. However, studies with humans have produced inconsistent findings. Although neurobehavioral abnormalities have been observed among cocaine-exposed infants in several studies and in some cases dose-response effects have been found, the specific neurobehaviors affected vary from one study to the next. Researchers studying the effects of fetal cocaine-exposure are faced with many difficult challenges. For example, women who use cocaine typically use other substances in addition to cocaine, many of the methods available for identifying cocaine-exposed neonates are not reliable, and the available methods for assessing cocaine-exposed newborns may not be sufficiently sensitive to detect the subtle effects of cocaine on the developing central nervous system. Despite these difficulties, there is a growing body of research that suggests that fetal cocaine exposure is associated with subsequent language deficits among children exposed in utero. However, it is virtually impossible to disentangle the effects of the impoverished environments in which these children are often raised from the effect, if any, of fetal cocaine exposure. To determine the effects of fetal cocaine exposure independent of postnatal environmental effects, cocaine-exposed neonates would ideally be tested within the first few weeks of birth, and to identify early risks for subsequent language delay, well-researched auditory information processing measures could be used. OBJECTIVE: The purpose of the present study was to assess the effects of fetal cocaine exposure on neonatal auditory information processing ability. To overcome limitations of some previous studies on the neuroteratogenic effects of cocaine, such as unreliable subject identification techniques, inadequate control over confounding variables, and questionable measures of central nervous system integrity, a valid measure of auditory information processing was used in a rigorous, case-control design. METHOD: Newborn information processing was assessed using habituation and recovery of head-turning toward an auditory stimulus across the 3 phases of the procedure: familiarization, novelty, and dishabituation. During the familiarization phase, the infant orients and habituates to a repeated word; during the novelty phase, the infant recovers head-turning to a novel word and subsequently habituates to this word; and during the dishabituation phase the infant displays renewed head-turning to the return of the original stimulus. Testing takes approximately 20 minutes. This procedure has been shown previously to discriminate among infants at high-, moderate-, and low-risk for subsequent developmental delay. Twenty-five cocaine-exposed and 25 nonexposed control neonates, identified by meconium analysis, urine analysis, and/or maternal self-report, were tested on the auditory information processing procedure. The majority of infants were tested within the first few days of birth. Cocaine-exposed and control neonates were matched on birth weight, gestational age, Apgar scores, age at testing, and socioeconomic status as reflected by household income. Mothers were matched on age, weight gain, cigarette smoking, and alcohol consumption. RESULTS: Fetal cocaine exposure was associated with impaired auditory information processing. Both cocaine-exposed and nonexposed control neonates oriented to the familiarization stimulus, but cocaine-exposed neonates displayed impaired habituation. Moreover, cocaine-exposed neonates did not recover or habituate to the novel stimulus or dishabituate to the return of the familiarization stimulus. (ABSTRACT TRUNCATED)

Introduction to the special section: studying intergenerational continuity and the transfer of risk.

This special section, "Longitudinal Studies of Intergenerational Continuity and the Transfer of Psychosocial Risk," examines the continuity of behavior across generations and the processes whereby parental characteristics, history, and experiences may place offspring at risk for various social, psychological, and health problems. The 8 prospective longitudinal studies in this section were initiated during the childhood of the parental generation and followed these individuals over time to the formation of new families. Topics include prediction of aggression, difficult temperament, social withdrawal, smoking, low academic achievement and high school dropout, adolescent parenthood, problematic fertility and birth circumstances, spousal violence, and problematic parenting practices. Predictors of successful adaptation to high-risk backgrounds and environments are examined, with an emphasis on protective factors and multiple determinants of outcomes.

Intergenerational transfer of psychosocial risk in women with childhood histories of aggression, withdrawal, or aggression and withdrawal.

Intergenerational transfer of risk between mothers and children, based on mothers' childhood aggression and social withdrawal, was examined in an inner-city sample. Each of the 3 studies reported involved a subset of the 909 female participants in the Concordia Longitudinal Risk Project, initiated when the participants were of school age. Using medical records, Study 1 (n = 853) focused on prediction of teen motherhood, delivery complications during childbirth, multiparity, and close spacing of births. Study 2 (n = 428) examined pathways to school dropout and teen parenthood. Study 3 (n = 89) involved prediction of observed parent and child behavior from mothers' childhood characteristics. Mothers' childhood aggression was consistently predictive of negative outcomes in each area of intergenerational risk, especially when combined with social withdrawal and low levels of academic achievement. Education was protective: Mothers' years of schooling predicted positive outcomes.

Spectral characterization of fluorescently labeled catechol estrogen 3,4-quinone-derived N7 guanine adducts and their identification in rat mammary gland tissue.

The oxidation of carcinogenic 4-hydroxycatechol estrogens (CE) of estrone (E1) and estradiol (E2) to catechol estrogen 3,4-quinones (CE-3,4-Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts [Cavalieri et al. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 10937]. These DNA adducts, 4-OHE1-1-N7Gua and 4-OHE2-1-N7Gua, are nonfluorescent. To utilize laser-excited fluorescence methods, the catechol estrogen-derived metabolites and adducts were labeled with a fluorescent marker. The 4-OHEi-1-N7Gua adduct standards (i = 1, 2) and 4-OHEi metabolites have been derivatized with 1-pyrenesulfonyl chloride and investigated by low-temperature spectroscopy under non-line-narrowing and line-narrowing conditions. Molecular modeling studies assisted in interpretation of the fluorescence spectra; energetically favored structures of the 4-OHE2-1-N7Gua-dipyrene adduct and 4-OHE2-dipyrene metabolite reveal unique conformations which, in agreement with fluorescence data, show a significant pi-pi interaction of pyrene labels with guanine and/or the aromatic ring of catechol estrogen. The conformation obtained for the 4-OHE2-1-N7Gua-dipyrene adduct appears to be conducive to mixing of its pipi state with pyrene-guanine charge-transfer states, consistent with the experimentally observed strong electron-phonon coupling. Non-line-narrowed and line-narrowed spectra obtained at 77 and 4.2 K, respectively, are shown to distinguish 4-OHE2-1-N7Gua-dipyrene adducts from 4-OHE2-dipyrene metabolites. These standards have subsequently been used for the spectroscopic identification of depurinating DNA adducts formed in a tissue culture experiment where rat mammary gland tissue was treated with the estrogen quinone E2-3,4-Q. The depurinating adduct formed is 4-OHE2-1-N7Gua.

Synthesis and structure elucidation of estrogen quinones conjugated with cysteine, N-acetylcysteine, and glutathione.

Catechol estrogen quinones (CE-Q) have been implicated as ultimate carcinogenic metabolites in estrogen-induced carcinogenesis. CE-Q may covalently bind to DNA to initiate cancer. These quinones can also be conjugated with glutathione, a reaction that prevents damage to DNA by CE-Q. The glutathione conjugates are then catabolized through mercapturic acid biosynthesis to cysteine and N-acetylcysteine conjugates. This may be the most important detoxification pathway of CE-Q. The chemical synthesis and characterization of these conjugates are the first essential steps to better understand their function in biological systems. Eighteen conjugates were synthesized by reaction of estrone-3,4-quinone (E1-3, 4-Q), estradiol-3,4-quinone (E2-3,4-Q), estrone-2,3-quinone (E1-2, 3-Q), or estradiol-2,3-quinone (E2-2,3-Q) with various sulfur nucleophiles, RSH, in which R is the cysteine, N-acetylcysteine, or glutathione moiety. Reactions of E1-3,4-Q and E2-3,4-Q produce regiospecifically 4-OHE1-2-SR and 4-OHE2-2-SR, respectively, in almost quantitative yield. E1-2,3-Q and E2-2,3-Q react regioselectively and quantitatively to form 2-OHE1(E2)-1-SR and 2-OHE1(E 2)-4-SR, in which the 1-isomers are always the major products. The ratio between 1 and 4 isomers is 3.5 for cysteine, 2.7 for N-acetylcysteine, and 2.5 for glutathione. The synthesized conjugates will be used as standards in the identification of these compounds formed in biological systems.

Novel glycopeptide antibiotics: N-alkylated derivatives active against vancomycin-resistant enterococci.

LY264826 (A82846B) is a naturally-occurring glycopeptide antibiotic, differing from vancomycin in the stereochemistry of the amino-sugar of the disaccharide function, and the presence of a third sugar attached at the benzylic position of amino acid residue 6. Despite these seemingly subtle differences, LY264826 is approximately 10 times more active than vancomycin against the enterococci. In the pursuit of new antibiotics active against multiresistant Gram-positive organisms, an extensive side chain SAR was developed focusing on the reductive alkylation of LY264826 at the amino function of the disaccharide moiety. A new series of derivatives having varying degrees of structural diversity in the side chain (e.g. varying lengths and degrees of rigidity) was found to have potent activity against vancomycin-resistant enterococci (MIC's < 1.0 microgram/ml) as well as activity against staphylococci and streptococci as good or better than vancomycin.

Metabolic activation and formation of DNA adducts of hexestrol, a synthetic nonsteroidal carcinogenic estrogen.

Hexestrol (HES), a synthetic nonsteroidal estrogen, is carcinogenic in Syrian golden hamsters. The major metabolite of HES is its catechol, 3'-OH-HES, which can be metabolically converted to the electrophilic catechol quinone, HES-3',4'-Q, by peroxidases and cytochrome P450. Standard adducts were synthesized by reacting HES-3',4'-Q with dG and dA to produce the adducts 3'-OH-HES-6'(alpha, beta)-N7Gua and HES-3',4'-Q-6'-N6dA, respectively. When HES-3',4'-Q was reacted with calf thymus DNA, 3'-OH-HES-6'(alpha,beta)-N7Gua was identified by HPLC and tandem mass spectrometry as the depurinating adduct, with minor amounts of stable adducts. 3'-OH-HES was bound to DNA after activation by horseradish peroxidase, lactoperoxidase, or rat liver microsomes. The depurinating adduct 3'-OH-HES-6'(alpha, beta)-N7Gua was identified in these systems at levels of 65, 41, and 11 micromol/mol of DNA-P, respectively. Unidentified stable adducts were observed in much lower amounts and were quantified by the 32P-postlabeling method. Similarly to 3'-OH-HES, the catechol metabolites of the natural steroidal estrogens estrone (E1) and estradiol (E2), namely, 2-OHE1, 4-OHE1, 2-OHE2, and 4-OHE2, can be oxidized to their corresponding quinones by peroxidases and cytochrome P450. The quinones of the carcinogenic 4-OHE1 and 4-OHE2 have chemical and biochemical properties similar to those of HES-3',4'-Q. The results suggest that formation of HES-3',4'-Q may be a critical event in tumor initiation by HES and that HES is an excellent model compound to corroborate the hypothesis that estrogen-3,4-quinones are ultimate carcinogenic metabolites of the natural steroidal estrogens E1 and E2.

Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators.

Cancer is a disease that begins with mutation of critical genes: oncogenes and tumor suppressor genes. Our research on carcinogenic aromatic hydrocarbons indicates that depurinating hydrocarbon-DNA adducts generate oncogenic mutations found in mouse skin papillomas (Proc. Natl. Acad. Sci. USA 92:10422, 1995). These mutations arise by mis-replication of unrepaired apurinic sites derived from the loss of depurinating adducts. This relationship led us to postulate that oxidation of the carcinogenic 4-hydroxy catechol estrogens (CE) of estrone (E1) and estradiol (E2) to catechol estrogen-3,4-quinones (CE-3, 4-Q) results in electrophilic intermediates that covalently bind to DNA to form depurinating adducts. The resultant apurinic sites in critical genes can generate mutations that may initiate various human cancers. The noncarcinogenic 2-hydroxy CE are oxidized to CE-2,3-Q and form only stable DNA adducts. As reported here, the CE-3,4-Q were bound to DNA in vitro to form the depurinating adduct 4-OHE1(E2)-1(alpha,beta)-N7Gua at 59-213 micromol/mol DNA-phosphate whereas the level of stable adducts was 0.1 micromol/mol DNA-phosphate. In female Sprague-Dawley rats treated by intramammillary injection of E2-3,4-Q (200 nmol) at four mammary glands, the mammary tissue contained 2.3 micromol 4-OHE2-1(alpha, beta)-N7Gua/molDNA-phosphate. When 4-OHE1(E2) were activated by horseradish peroxidase, lactoperoxidase, or cytochrome P450, 87-440 micromol of 4-OHE1(E2)-1(alpha, beta)-N7Gua was formed. After treatment with 4-OHE2, rat mammary tissue contained 1.4 micromol of adduct/mol DNA-phosphate. In each case, the level of stable adducts was negligible. These results, complemented by other data, strongly support the hypothesis that CE-3,4-Q are endogenous tumor initiators.

Production of hybrid glycopeptide antibiotics in vitro and in Streptomyces toyocaensis.

BACKGROUND: The glycopeptide antibiotics vancomycin and teicoplanin are currently the last line of defence against some microorganisms that are resistant to many drugs. The emergence of vancomycin-resistant and teicoplanin-resistant enterococci underscores the need for more potent antibiotics. The glycosylation patterns of glycopeptides and chemical modifications of the glycosyl moieties have been shown to greatly influence their antibiotic activity, and certain combinations have resulted in highly active new compounds. To explore further the production of more potent glycopeptide antibiotics, we assessed whether glycosyltransferases could be used to produce hybrid compounds that contain various combinations of sugars and peptide cores. RESULTS: We cloned five glycosyltransferase genes from Amycolatopsis orientalis strains that produce vancomycin or a related glycopeptide, A82846. The gtfB and gtfE' genes from A. orientalis strains expressed in Escherichia coli produced glucosyltransferase activities that added glucose or xylose to the vancomycin heptapeptide. The GtfE' protein added glucose efficiently to two other heptapeptides related to teicoplanin to produce hybrid glycopeptide antibiotics. The cloned gtfE' gene, driven by the strong constitutive promoter ermEp*, was introduced into Streptomyces toyocaensis, which produces the antibiotic A47934, a heptapeptide related to teicoplanin; recombinant organisms produced glucosyl A47934, a hybrid glycopeptide antibiotic. CONCLUSIONS: Cloned glycosyltransferases from glycopeptide antibiotic producers can be used to produce novel hybrid antibiotics, both in vitro and in vivo. Because similar enzymes have differing degrees of substrate specificity, it is advantageous to characterize the substrate specificity with enzymes expressed in E. coli prior to constructing recombinant actinomycetes for production.

Production of a high-affinity monoclonal antibody specific for 7-(benzo[alpha]pyren-6-yl) guanine and its application in a competitive enzyme-linked immunosorbent assay.

Molecular dosimetry of depurinating DNA adducts of benzo[alpha]pyrene (BP) is a promising new approach to measurement of cancer risk associated with exposure to polycyclic aromatic hydrocarbons (PAH). Depurinating adducts of BP are spontaneously released from DNA and can be detected in urine. As a first step toward developing a monoclonal antibody (MAb)-based molecular dosimetry for depurinating DNA adducts of BP, a MAb (MAb CB53) has been produced with high specific affinity for 7-(benzo[alpha]pyren-6-yl)guanine (BP-6-N7Gua), a major depurinating adduct of BP. Production of this MAb was dependent on the successful synthesis of an effective immunogen consisting of the hydrophobic BP-6-N7Gua coupled to carrier protein via a rigid spacer arm. A competitive enzyme-linked immunosorbent assay (ELISA) for BP-6-N7Gua has been developed with MAb CB53 and has been applied to evaluation of MAb binding and to quantitation of BP-6-N7Gua in a biological sample. The MAb binds with high affinity to BP-6-N7Gua (Ka = 1.4 x 10(8) M-1) and to BP-6-N7Ade (Ka = 0.7 x 10(8) M-1), another major depurinating DNA adduct of BP, but discriminates well between BP and BP-6-N7Gua. BP-6-N7Gua produces 50% inhibition at 750 fmol in the competitive ELISA, whereas BP produces 50% inhibition at 960 000 fmol. Binding affinities to selected PAH, BP-DNA adducts, and BP metabolites indicate significant contributions of the hydrophobic region C-3, C-4, and C-5 of BP and the polar oxygen of guanine to MAb/adduct binding. In a preliminary test of the utility of the competitive ELISA for quantitation of BP-6-N7Gua in urine samples, the assay (sensitivity: 200 fmol per well) produced an accurate determination of the adduct added to normal human urine.

Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides.

Estrogens can have two roles in the induction of cancer: stimulating proliferation of cells by receptor-mediated processes, and generating electrophilic species that can covalently bind to DNA. The latter role is thought to proceed through catechol estrogen metabolites, which can be oxidized to o-quinones that bind to DNA. Four estrogen-deoxyribonucleoside adducts were synthesized by reaction of estrone 3,4-quinone (E1-3,4-Q), 17 beta-estradiol 3,4-quinone (E2-3,4-Q), or estrone 2,3-quinone (E1-2,3-Q) with deoxyguanosine (dG) or deoxyadenosine (dA) in CH3CO2H/H2O (1:1). Reaction of E1-3,4-Q or E2-3,4-Q with dG produced specifically 7-[4-hydroxyestron-1(alpha, beta)-yl]guanine (4-OHE1-1(alpha, beta)-N7Gua) or 7-[4-hydroxyestradiol-1(alpha, beta)-yl]-guanine (4-OHE2-1(alpha, beta)-N7Gua), respectively, in 40% yield, with loss of deoxyribose. These two quinones did not react with dA, deoxycytidine, or thymidine. When E1-2,3-Q was reacted with dG or dA, N2-(2-hydroxyestron-6-yl)deoxyguanosine (2-OHE1-6-N2dG, 10% yield) and N6-(2-hydroxyestron-6-yl)deoxyadenosine (2-OHE1-6-N6dA, 80% yield), respectively, were formed. These adducts provide insight into the type of DNA damage that can be caused by o-quinones of the catechol estrogens. The estrogen 3,4-quinones are expected to produce depurinating guanine adducts that are lost from DNA, generating apurinic sites, whereas the 2,3-quinones would form stable adducts that remain in DNA, unless repaired. The adducts reported here will be used as references in studies to elucidate the structure of estrogen adducts in biological systems.

Radical cations of benzo[a]pyrene and 6-substituted derivatives: reaction with nucleophiles and DNA.

1. Oxidation of benzo[a]pyrene (BP) by I2 in the presence of AgClO4 in benzene generates the BP.+ClO4-.AgI complex. This same method was used to produce radical cations from 6-FBP, 6-ClBP, 6-BrBP and 6-CH3BP. 2. Reaction of the BP, 6-FBP, 6-ClBP and 6-BrBP radical cation perchlorates with H2O produced BP 1,6-, 3,6- and 6,12- dione, whereas 6-CH3BP.+ClO4-.AgI yielded 6-CH2OHBP. 3. When BP.+ClO4-.AgI and 6-FBP.+ClO4-.AgI were reacted with NaOAc in H2O/CH3CN (9:1), 6-OAcBP was formed, in addition to the quinones. In the case of 6-ClBP.+ClO4-.AgI, a small amount of 1-OAc-6-ClBP and 3-OAc-6-ClBP was formed in addition to the diones, whereas for 6-BrBP and 6-CH3BP the reaction products were BP diones and 6-CH2OHBP respectively. 4. These results confirm the localization of charge in the BP.+ at C-6, followed by C-1 and C-3. 5. The reaction of BP with NOBF4 in CH2Cl2 produced BP.+BF4-, radical cation free of complexation with inorganic salts. 6. Reaction of BP.+BF4- with DNA produced the depurinating adducts BP-6-C8Gua, BP-6-C8dGua and BP-6-N7Gua.