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Biomedical subjects

D E Williams

Publications and source records attributed to D E Williams.

At least 127 records · Page 7Linked to original sources
PubMed1995

Medical and economic costs of psychologic distress in patients with coronary artery disease.

OBJECTIVE: To determine the effect of psychologic distress, measured with a commonly used screening questionnaire, on 6-month morbidity and rehospitalization costs in coronary patients. DESIGN: Psychologic distress was determined by screening with the Symptom Checklist-90--Revised (SCL-90-R) self-report inventory during the second week of cardiac rehabilitation. Costs associated with cardiovascular rehospitalization during a 6-month follow-up period were recorded, and differences between "distressed" and "nondistressed" patients were analyzed statistically. MATERIAL AND METHODS: The study cohort consisted of 381 patients (311 men and 70 women) referred for cardiac rehabilitation after an index hospitalization for unstable angina, myocardial infarction, coronary angioplasty, or coronary bypass procedure. Patients with SCL-90-R scores above the 90th percentile for outpatient adults were considered distressed (N = 41); patients with scores below this level were considered nondistressed (N = 340). RESULTS: The 6-month follow-up was complete in all but 1 of the 381 patients. Distressed patients had significantly higher rates of cardiovascular rehospitalization, any recurrent events, and recurrent "hard events" (cardiac death, myocardial infarction, or cardiac arrest and resuscitation) within 6 months after dismissal from their index hospitalization in comparison with nondistressed patients. Adjustment for other factors associated with a risk of early rehospitalization and recurrent events did not reduce the strength or significance of the association between psychologic distress and early cardiovascular rehospitalization or recurrent events. The mean rehospitalization costs were significantly higher in the distressed than in the nondistressed patients ($9,504 versus $2,146). CONCLUSION: These data add support to the hypothesis that psychologic distress adversely affects the prognosis in coronary patients, confirm the added morbidity and rehospitalization costs attributable to psychologic distress, and suggest the potential for improving the prognosis in selected coronary patients by identification and appropriate treatment of psychologic distress.

Adaptation, Psychological↗
PubMed1995

Tissue-specific expression of flavin-containing monooxygenase (FMO) forms 1 and 2 in the rabbit.

The microsomal flavin-containing monooxygenases (FMO) represent a family of xenobiotic-metabolizing enzymes with distinct tissue- and species-specific patterns of expression. Expression for two FMO isoforms (FMO1 and FMO2) in rabbit was characterized by determining mRNA levels, protein levels and catalytic activity in male and female liver, lung, kidney, esophagus, intestine, nasal mucosa (maxilloturbinates and ethmoturbinates) and gonadal tissue. Northern blot hybridization analyses performed with cDNA probes for each isoform showed marked differences in mRNA expression between tissues: FMO1 expression was highest in liver and intestine, followed by ethmoturbinates, maxilloturbinates and low but detectable levels in female kidney; FMO2 expression was highest in lung, followed by maxilloturbinates, ethmoturbinates, esophagus and kidney. More sex-related differences were observed for FMO2, with higher levels of mRNA in female esophagus, nasal mucosa and kidney. Western blot analyses showed similar patterns of expression at the protein level. Microsomal catalytic activities determined by [14C]-DMA N-oxide formation also indicated tissue- and sex-related differences in substrate metabolism by FMO. Analysis of tissue-specific FMO catalytic activity was also performed using thiocarbamides as isoform-specific probes. Microsomes from those tissues containing FMO2, but not FMO1, failed to catalyze oxidation of the larger (van der Waals surface area greater than 178 A) FMO1-specific thiocarbamides. The results of this study demonstrate that tissue-specific control mechanisms play a more dominant role in the overall constitutive regulation of FMO than other potential factors, such as hormonal influences. Elucidation of the mechanisms controlling FMO tissue-specific expression will lead to a better understanding of target organ specificity for xenobiotic detoxication or bioactivation.

Animals↗
PubMed1995

Mechanisms of tumor modulation by indole-3-carbinol. Disposition and excretion in male Fischer 344 rats.

This study describes the disposition and excretion of indole-3-carbinol (I3C), a natural dietary tumor modulator and candidate chemopreventive agent, in male Fisher 344 rats after continuous dietary or a single oral administration. Steady-state urinary and fecal excretion were attained 40 and 112 hr, respectively, after commencing continuous exposure. These two routes accounted for approximately 75% of the administered dose, of which 77% appeared in feces. After 7 days of 2,000 ppm dietary I3C, a mean of 1,154 microM I3C eq was found in liver, of which 17% was present as extractable, unbound I3C derivatives. Total equivalents in liver decreased to 643 and 411 microM 24 and 48 hr later, respectively, for animals returned to control diet. Mean levels of I3C eq in lung decreased from 436 to 219 microM, and blood levels decreased from 320 to 208 microM over the same 48-hr period. After administration of 1 mmol/kg radioinert I3C (a comparable daily dose as in the feeding study) for 6 days, animals were given 1 mmol/kg [3H]I3C. Mean liver levels were 257, 283, and 541 microM I3C eq at 1.5, 3, and 6 hr after dosing, and these levels represented 0.97%, 1.34%, and 2.45% of the total I3C dose administered, respectively. Concentrations of I3C eq changed little in blood, kidney, tongue, or lung over this time period. HPLC analysis of ethyl acetate extracts of liver from rats given an oral dose revealed 24 distinct [3H]I3C-derived peaks. Two of the predominant peaks were identified as 3,3'-diindolylmethane (I33', a linear dimer of I3C) and [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LT, a linear trimer). A novel I3C metabolite was identified as 1-(3-hydroxymethyl)-indolyl-3-indolylmethane (HI-IM). Hepatic levels of these metabolites and three major, but unidentified, products were between 1.0 and 13.1 microM; highest levels were observed at 6 hr or, for HI-IM, at 1.5 hr postdosing. Parent I3C was not detected in liver extracts, whereas the potent Ah receptor agonist 3,2-b-indolocarbazole (ICZ) was estimated at 1.6 nM. These data suggest that neither I33', LT, or ICZ alone reach sufficient hepatic concentration to account for cytochrome P450IA induction by dietary I3C, or provide effective inhibition of microsomal bioactivation of the hepatocarcinogen aflatoxin B1; however, the total hepatic mixture of I3C derivatives may be sufficient to provide both modulatory responses in the rat.

Administration, Oral↗
PubMed1994

Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice.

Interleukin 7 (IL-7) stimulates the proliferation of B cell progenitors, thymocytes, and mature T cells through an interaction with a high affinity receptor (IL-7R) belonging to the hematopoietin receptor superfamily. We have further addressed the role of IL-7 and its receptor during B and T cell development by generating mice genetically deficient in IL-7R. Mutant mice display a profound reduction in thymic and peripheral lymphoid cellularity. Analyses of lymphoid progenitor populations in IL-7R-deficient mice define precisely those developmental stages affected by the mutation and reveal a critical role for IL-7R during early lymphoid development. Significantly, these studies indicate that the phase of thymocyte expansion occurring before the onset of T cell receptor gene rearrangement is critically dependent upon, and mediated by the high affinity receptor for IL-7.

Animals↗
PubMed1994

Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines.

CD30 is a member of the tumor necrosis factor receptor superfamily. CD30 was originally described as a cell surface antigen on primary and cultured Hodgkin's and Reed-Sternberg cells. In this study, recombinant human CD30 ligand was expressed on the surface of CV-1/EBNA cells and tested for biologic activities on a variety of different CD30+ human lymphoma cell lines. CD30 ligand enhanced Ig secretion of Epstein-Barr virus (EBV)-immortalized, CD30+ lymphoblastoid B-cell lines, but not Burkitt lymphoma lines. Recombinant CD30 ligand enhanced proliferation of "T-cell-like" Hodgkin's disease-derived cell lines and an adult T-cell leukemia cell line, but not "B-cell-like" Hodgkin's disease-derived cell lines, CD30+, EBV-immortalized lymphoblastoid B-cell lines, or CD30+ and EBV+ tumor B-cell non-Hodgkin's lymphoma cell lines. In addition, CD30 ligand mediated reduction of proliferation and viability, by induction of cytolytic cell death, of CD30+, large-cell anaplastic lymphoma cell lines. Two new antibodies, M44 and M67, against the CD30 antigen demonstrated similar biologic activities to the CD30 ligand. Taken together, these data demonstrate pleiotropic biologic activities of the CD30 ligand on different CD30+ lymphoma cell lines and indicate that the CD30-CD30 ligand interaction might have a pathophysiologic role in Hodgkin's and some non-Hodgkin's lymphomas.

Antibodies, Monoclonal↗
PubMed1994

Steel factor (c-kit ligand) stimulates the in vitro growth of immature CD3-/CD4-/CD8- thymocytes: synergy with IL-7.

The ability of Steel factor (SLF) to stimulate the growth of immature thymocytes alone and in combination with IL-7 was assessed. In suspension cultures of CD4-/CD8- thymocytes, SLF itself did not induce significant proliferation, but in combination with IL-7, it induced a greater response than did IL-7 alone. In fetal thymus lobe submersion cultures, SLF stimulated the growth of cells to a magnitude similar to that of IL-7 and the combination resulted in a synergistic response. Phenotypic analysis of these cells revealed that SLF in comparison to IL-7 stimulated the growth of a less mature population. The synergistic growth stimulated by the combination of IL-7 and SLF occurred in a population of IL-2R+/CD4-/CD8-/CD3- cells. Cells grown in SLF expressed low levels of IL-2R and overnight culture in IL-7 dramatically increased IL-2R expression. Thus, these results are consistent with the hypothesis that SLF stimulates the growth of a less mature thymocyte population than does IL-7.

Animals↗
PubMed1994

The mammalian flavin-containing monooxygenases: molecular characterization and regulation of expression.

The flavin-containing monooxygenase (FMO) has been characterized in several mammalian species, including human. The FMO forms a stable NADP(H)- and oxygen-dependent 4 alpha-hydroperoxy flavin enzyme intermediate in the absence of an oxygenatable substrate. As such, substrate specificity appears to be controlled by access to this stabilized intermediate, resulting in this enzyme's ability to metabolize a wide variety of xenobiotics. These include tertiary and secondary alkyl- and arylamines, many hydrazines, thiocarbamides, thioamides, sulfides, disulfides, thiols, and other soft nucleophiles. Although some of these compounds are oxidized to less active derivatives, several examples of metabolic activation to potentially toxic intermediates also exist. Mercapto-pyrimidines and thiocarbamides, for example, appear to be activated predominantly by FMO. Thus, this enzyme system may play an important role in the early steps of chemical toxicity. Often, the contribution of FMO to the metabolism of a given compound can be assessed by its unique stereoselectivity relative to other oxygenases. For example, the cytochromes P450 oxidize (S)-nicotine to a mixture of cis- and trans-N-1'-oxides. In contrast, (S)-nicotine is oxidized by human FMO3 exclusively to the trans-N-1'-oxide. With the purification and cloning of FMO from multiple tissues and species it became apparent that more than one FMO exists. Further, there are considerable tissue- and species-specific differences in FMO expression that likely contribute to observed differences in detoxication competency and toxicant susceptibility.

Animals↗
PubMed1994

Optimizing the effectiveness of hematopoietic growth factors.

Hematopoiesis is regulated in a very precise fashion by a balance between both positive and negative growth factor signals in the hematopoietic microenvironment. Many of these growth factor signals have been identified and are available as recombinant proteins. At the present time, the approved uses for hematopoietic growth factors involve their use to facilitate blood cell production in situations of hematopoietic suppression or in cases where endogenous growth factor production is inappropriately low. Recent studies with the hematopoietic growth factors are looking at innovative strategies for their use and new clinical situations in which to evaluate their effectiveness. This review looks at some of these new uses for hematopoietic growth factors.

Animals↗
PubMed1994

Treatment and extended follow-up of chronic hand mouthing.

This study evaluated the relative effectiveness of differential reinforcement of other behaviors (DRO), differential reinforcement of incompatible behavior (DRI), and contingent watermist (CWM) in treating chronic self-injurious hand mouthing. The participant, a man with profound mental retardation, lived in a large residential facility. Prior to treatment he had participated in ineffective nonaversive treatments and was continuously mechanically restrained by his attending physician to promote healing of his hands. Baseline data collected in daily 30-minute sessions showed a hand mouthing rate of 1.5 responses/minute. Implementing the DRO, DRI, and CWM procedures in combination resulted in an initial 85% rate reduction. Each treatment component subsequently was withdrawn and reintroduced systematically in order to evaluate its relative effective upon hand mouthing. Only CWM plus differential reinforcement (DRO and/or DRI) had a significant effect upon hand mouthing. DRO plus DRI procedures were ineffective. In an effort to promote generalization of treatment effects, subsequent manipulations evaluated the effects of therapist proximity to the participant (one foot, 21 feet, or a random distance between one and 21 feet). Hand mouthing rates were reliably lower in the one-foot condition than in the 21-feet condition. The random proximity condition produced an intermediate performance. Direct care staff have implemented the DRI and CWM procedures throughout the participant's waking hours for nearly 3 years with almost complete elimination of hand mouthing.

Adult↗
PubMed1994

The isolation of a fibroblast growth inhibitor associated with perigraft seroma.

PURPOSE: Perigraft seroma is a rare complication of reconstructive vascular surgery characterized by a clear, sterile fluid collection confined within a fibrous pseudomembrane around a prosthetic graft. The exact cause of this disease is unknown but involves failure of surrounding connective tissue to incorporate the graft. To understand why this occurs, we studied sera from patients with perigraft seroma for their effect on human fibroblasts. Sera from control subjects, patients with uninfected prosthetic grafts, and patients with prosthetic grafts were tested for comparison. METHODS: Fibroblast growth was measured by radioactive thymidine uptake and hexosaminidase colorimetric cell proliferation assays. We fractionated sera with gel filtration columns and measured each fraction's effect on fibroblast growth. RESULTS: Serum samples from patients with perigraft seroma inhibited fibroblast growth in a dose-dependent manner. In contrast, a postseroma sample, normal human sera, and sera from patients with infected and uninfected grafts showed no significant fibroblast inhibition. An inhibitory factor with a molecular weight of 2000 d was isolated from serum of patients with perigraft seroma. CONCLUSIONS: Perigraft seroma is associated with a fibroblast inhibitor with a molecular weight of 2000 d. Further identification and characterization of this protein may lead to clinical applications in preventing and treating perigraft seroma.

Blood Vessel Prosthesis↗
PubMed1994

Computed tomographic diagnosis of Mycobacterium avium-intracellulare complex in patients with bronchiectasis.

We tested the hypothesis that bronchiectasis and multiple small lung nodules seen on chest computed tomography (CT) are indicative of Mycobacterium avium-intracellulare complex (MAC) infection or colonization by reviewing CT scans and histories of 100 outpatients with CT diagnosis of bronchiectasis. Of the 24 patients with multiple pulmonary nodules, 19 had lung nodules and bronchiectasis in the same lobe. Mycobacterial cultures were performed on 63 of the 100 patients, including 15 of the 24 patients with lung nodules and 48 of the 76 patients with no lung nodules. Of the 15 patients with lung nodules, 8 (53 percent) had cultures positive for MAC, as did 2 of the 48 (4 percent) patients with no CT evidence of lung nodules. The number of cultures positive for fungi was approximately the same in both groups. In our outpatient population, CT prediction of cultures positive for MAC in bronchiectatic patients with multiple small lung nodules has a sensitivity of 80 percent, a specificity of 87 percent, and an accuracy of 86 percent.

Adolescent↗
PubMed1994

Causal attribution and affective response as mediated by task performance and self-acceptance.

Predictions derived from cognitive consistency theories, self-esteem theories, and ego-serving-bias theory concerning how students would make attributional and affective responses to their academic performance were investigated. 202 university students completed a measure of self-acceptance of their college ability and made attributional and affective responses to an hypothetical examination performance. Analyses showed that students receiving positive feedback perceived greater internal causality and responded with greater positive affect than students receiving negative feedback. Self-acceptance did not moderate the attributions or affective reactions. The results supported the ego-serving-bias theory and provided partial support for self-esteem theory. Findings did not support predictions from cognitive-consistency theory.

Adult↗
PubMed1994

Mast cell growth factor enhances multilineage hematopoietic recovery in vivo following radiation-induced aplasia.

Based on in vitro studies, mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has been implicated as an important hematopoietic regulator, especially in the presence of additional hematopoietic cytokines. Since hematopoietic regeneration follows sublethal radiation-induced hematopoietic injury and is thought to be mediated by endogenously produced cytokines, the ability to accelerate recovery from radiation-induced hematopoietic hypoplasia was used to evaluate in vivo effects of MGF administration. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of 60Co radiation followed by subcutaneous administration of either saline or 100, 200, or 400 micrograms/kg/d recombinant murine MGF on days 1 to 17 postirradiation. Recoveries of bone marrow and splenic spleen colony-forming units (CFU-S), granulocyte-macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC), and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF accelerated hematopoietic recovery at the 100 and 200 micrograms/kg/d doses. The 100 micrograms/kg/d dose accelerated recovery of only GM-CFC, while the 200 micrograms/kg/d dose accelerated CFU-S, GM-CFC, WBC, and PLT recoveries. In contrast, hematopoietic recovery was delayed in mice receiving the 400 micrograms/kg/d dose. These studies demonstrate the in vivo dose-dependent ability of MGF to accelerate multilineage hematopoietic regeneration following radiation-induced hematopoietic hypoplasia. They also document detrimental effects of providing "supraoptimal" doses of this growth factor and suggest caution in dose-escalation trials in humans.

Animals↗
PubMed1994

The flt3 ligand: a hematopoietic stem cell factor whose activities are distinct from steel factor.

A number of growth factors have been described that affect the hematopoietic system. Among this group are Steel factor (also known as mast cell growth factor, stem cell factor and kit ligand), and the more recently described flt3 ligand. These factors have been shown to function by binding to and activating the c-kit and flt3 tyrosine kinase receptors, respectively. Both of these factors stimulate the growth of mouse and human hematopoietic progenitor cells. These factors therefore differ from such later acting hematopoietic factors as colony-stimulating factor (CSF)-1, which regulates the growth, survival and differentiation of monocytic cells through the c-fms tyrosine kinase receptor. Like Steel factor, the flt3 ligand has little biological activity on its own, but synergizes well with a number of other colony stimulating factors and interleukins. One major difference between the two factors appears to be their effect on mast cells. Steel factor stimulates both the proliferation and activation of mast cells, while preliminary data with the flt3 ligand suggests that it has no effect on mast cells. Although the flt3 ligand and Steel factor each act on early hematopoietic cells, differences in their activities suggest that they are not redundant and are both required for normal hematopoiesis.

Animals↗
PubMed1994

A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells.

A thymic stromal cell line with a medullary phenotype (Z210R.1) supported the differentiation of surface IgM+ B cells when cocultured with fetal liver cells in vitro. Conditioned medium (CM) from this cell line supported the long-term growth of a B cell line (NAG8/7) isolated from cocultures and enhanced the proliferation of unfractionated thymocytes to suboptimal concentrations of anti-CD3 antibodies in vitro. Biological assays of the CM detected interleukin-7 (IL-7) but not IL-1, IL-2, IL-3, IL-4, IL-6, Steel factor (SCF), leukemia inhibitory factor (LIF), or macrophage or granulocyte colony-stimulating factors (M-CSF or G-CSF). The failure of recombinant IL-7 to maintain the long-term growth of NAG8/7 cells and the inability of anti-IL-7 antibodies to significantly affect the response of either NAG8/7 cells or thymocytes to CM suggested the presence of one or more other cytokines in the CM. Analysis of concentrated CM fractionated by anion exchange chromatography revealed a single peak of activity in the NAG8/7 assay with an elution profile that was distinct from IL-7. Two peaks of activity were detected in the thymocyte response to anti-CD3 antibodies; one corresponded to IL-7 and the other corresponded to the same fractions that stimulated NAG8/7 cells. The second peak of thymocyte stimulatory activity could not be inhibited by neutralizing anti-IL-7 antibodies. In addition to producing a cytokine with unique properties, this thymic stromal cell exhibits a functional homology to bone marrow or fetal liver stromal cells not previously appreciated.

Animals↗
PubMed1993

Combination protocols of cytokine therapy with interleukin-3 and granulocyte-macrophage colony-stimulating factor in a primate model of radiation-induced marrow aplasia.

Single cytokine therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) has been shown to be effective in decreasing the respective periods of neutropenia and thrombocytopenia following radiation- or drug-induced marrow aplasia. The combined administration of IL-3 and GM-CSF in normal primates suggested that a sequential protocol of IL-3 followed by GM-CSF would be more effective than that of GM-CSF alone in producing neutrophils (PMN). We investigated the therapeutic efficacy of two combination protocols, the sequential and coadministration of recombinant human IL-3 and GM-CSF relative to respective single cytokine therapy, and delayed GM-CSF administration in sublethally irradiated rhesus monkeys. Monkeys irradiated with 450 cGy (mixed fission neutron:gamma radiation) received either IL-3, GM-CSF, human serum albumin (HSA), or IL-3 coadministered with GM-CSF for days 1 through 21 consecutively postexposure, or IL-3 or HSA for days 1 through 7 followed by GM-CSF for days 7 through 21. All cytokines and HSA were injected subcutaneously at a total dose of 25 micrograms/kg/d, divided twice daily. Complete blood counts (CBC) and platelet (PLT) counts were monitored over 60 days postirradiation. The respiratory burst activity of the PMN was assessed flow cytometrically, by measuring hydrogen peroxide (H2O2) production. Coadministration of IL-3 and GM-CSF reduced the average 16-day period of neutropenia and antibiotic support in the control animals to 6 days (P = .006). Similarly, the average 10-day period of severe thrombocytopenia, which necessitated PLT transfusion in the control animals, was reduced to 3 days when IL-3 and GM-CSF were coadministered (P = .004). The sequential administration of IL-3 followed by GM-CSF had no greater effect on PMN production than GM-CSF alone and was less effective than IL-3 alone in reducing thrombocytopenia. PMN function was enhanced in all cytokine-treated animals.

Animals↗
PubMed1993

Covalent binding of (+) 7S-trans-7,8-dihydrobenzo [a]pyrene-7,8-diol to trout DNA: P-450- and peroxidation-dependent pathways.

Bioactivation in vivo of pure (+) 7S-trans-7,8-dihydrobenzo[a]pyrene- 7,8-diol ((+) BP-7,8-DHD) was investigated in rainbow trout. Embryos, microinjected with 0.01-1.0 microgram of [3H]-(-)-7S-trans-7,8-dihydrobenzo[a]-pyrene-7,8-diol-anti-9,10-epoxide ((-) anti-BPDE), exhibited a dose-dependent increase in DNA adduction. Subsequently, microinjection of trout embryos with [14C] (+) BP-7,8-DHD also demonstrated a dose-dependent increase in DNA adduction. To determine the relative contribution of P-450-dependent versus peroxidation-dependent epoxygenation of (+)-BP-7,8-DHD, trout embryos were co-injected with [14C]-(+)-BP-7,8-DHD and either beta-naphthoflavone (BNF) (CYP1A1 inducer) or carbon tetrachloride (CCl4) (lipid peroxidation enhancer). Co-injection with BNF tended to enhance covalent binding to DNA, which was consistent with rapid induction of CYP1A1. Co-injection with CCl4, significantly increased covalent binding of [14C]-(+)-BP-7,8-DHD to DNA, suggesting a contribution from non-enzymic cooxidation. 32P-Postlabeling analysis of liver DNA adducts following i.p. injections of (+) BP-7,8-DHD did not detect appreciable amounts of (-) anti-BPDE-dG from juvenile trout fed control diets or diets containing hydrogen peroxide or BNF. On the contrary, BNF pre-feeding markedly enhanced the levels of an adduct which co-chromatographed with authentic (+) syn-BPDE-dG. These results confirm that trout are capable of metabolically activating BP-DHD to the ultimate carcinogen BPDE and that BNF stimulates CYP1A1-dependent epoxygenation, but peroxidation-dependent activation may not contribute significantly to the bioactivation of BP-7,8-DHD in vivo.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗