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Pyrrolizidine alkaloids (PAs) are hepatotoxic, genotoxic, and carcinogenic phytochemicals. Upon metabolic activation, PAs produce dehydropyrrolizidine alkaloids (dehydro-PAs) as reactive primary pyrrolic metabolites. Dehydro-PAs are unstable, facilely hydrolyzed to (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5

The hepatotoxic pyrrolizidine alkaloids (PAs) are metabolically activated in the liver to form reactive dehydro-PAs, which generate pyrrole-protein adducts leading to hepatotoxicity. Monocrotaline, but not other PAs, is also pneumotoxic, supposedly due to the migration of the liver-generated corresponding dehydro-PA into the lung to form pyrrole-protein adducts to induce pneumotoxicity. The present study investigated whether other PAs are also pneumotoxic. Metabolic activation of four representative hepatotoxic PAs, monocrotaline, retrorsine, riddelliine and clivorine, was investigated using rat liver or lung S9 incubation. All PAs produced pyrrole-protein adducts significantly in rat liver S9 but negligible in lung S9 fraction, revealing that liver is the key organ responsible for metabolic activation generating dehydro-PAs. Furthermore, these four PAs and another two PAs present in the alkaloid extract of Gynura segetum, a widely used PA-producing herb responsible for human PA poisonings in China, were orally administered to rats using the same hepatotoxic dose of 0.2 mmol/kg. All six PAs induced pneumotoxicity in rats within 48 h. The results demonstrated that pneumotoxicity could be a common phenomenon of PAs and the liver-derived dehydro-PAs might move to the lung and form pyrrole-protein adducts, leading to pulmonary toxicity.

Combinations of semiconductor nanoparticles (NPs) with noble metal NPs enable an increase in the photoactivity of semiconductor NPs into the visible and near-infrared regions. The design ra...

Engineered nanomaterials may adversely impact human health and environmental safety by nano-bio-eco interactions not fully understood. Their interaction with biotic and abiotic environments are varied and complicated, ranging from individual species to entire ecosystems. Their behavior, transport, fate, and toxicological profiles in these interactions, addressed in a pioneering study, are subsequently seldom reported. Biological, chemical, and physical dimension properties, the so-called multidimensional characterization, determine interactions. Intermediate species generated in the dynamic process of nanomaterial transformation increase the complexity of assessing nanotoxicity. We review recent progress in understanding these interactions, discuss the challenges of the study, and suggest future research directions.

Many pyrrolizidine alkaloids (PAs) are hepatotoxic, genotoxic, and carcinogenic phytochemicals. Metabolism of PAs in vivo generates four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-DNA adducts that have been proposed to be responsible for PA-induced liver tumor formation in rats. In this present study, we determined that the same set of DHP-DNA adducts was formed upon the incubation of 7-glutathione-DHP and 7-cysteine-DHP with cultured human hepatocarcinoma HepG2 cells. These results suggest that 7-glutathione-DHP and 7-cysteine-DHP are reactive metabolites of PAs that can bind to cellular DNA to form DHP-DNA adducts in HepG2 cells, and can potentially initiate liver tumor formation.

Etheno-DNA adducts are generated by interaction of cellular DNA with exogenous environmental carcinogens and end products of lipid peroxidation. It has been determined that 1,N(6)-etheno-2'-deoxyadenosine (εdA) and 3,N(4)-etheno-2'-deoxycytidine (εdC) adducts formed in human white blood cells can be used to serve as biomarkers of genetic damage mediated by oxidative stress. In this study, we developed an ultrasensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method used to detect and quantify εdA and dC adducts in human white blood cells. The percent recoveries of εdA and dC adducts were found to be 88.9% ± 2.8 and 95.7% ± 3.7, respectively. The detection limits were ∼ 1.45 fmol for εdA and ∼ 1.27 fmol for εdC in 20 μg of human white blood cell DNA samples, both εdA and εdC adducts could be detected using only ∼ 5 μg of DNA per sample. For validation of the method, 34 human blood cell DNA samples were assayed and the results revealed a significant difference (P0.01) between levels (fmol/μg DNA) of 0.82 ± 0.83 (standard deviation [SD]) (range: 0.15-3.11) for εdA, 3.28 ± 3.15 (SD) (range: 0.05-9.6) for εdC in benzene-exposed workers; and 0.04 ± 0.08 (SD) (range: 0.0-0.27) for εdA and 0.77 ± 1.02 (SD) (range: 0.10-4.11) for εdC in non-benzene-exposed workers. Our method shows a high sensitivity and specificity when applied to small amounts of human white blood cell DNA samples; background levels of εdA and εdC could be reproducibly detected. The ultrasensitive and simple detection method is thus suitable for applications in human biomonitoring and molecular epidemiology studies.

Plants are used by humans in daily life in many different ways, including as food, herbal medicines, and cosmetics. Unfortunately, many natural plants and their chemical constituents are photocytotoxic and photogenotoxic, and these phototoxic phytochemicals are widely present in many different plant families. To date, information concerning the phototoxicity and photogenotoxicity of many plants and their chemical constituents is limited. In this review, we discuss phototoxic plants and their major phototoxic constituents; routes of human exposure; phototoxicity of these plants and their constituents; general mechanisms of phototoxicity of plants and phototoxic components; and several representative phototoxic plants and their photoactive chemical constituents.

Comfrey has been consumed by humans as a vegetable and a tea and used as an herbal medicine for more than 2000 years. Comfrey, however, produces hepatotoxicity in livestock and humans and carcinogenicity in experimental animals. Comfrey contains as many as 14 pyrrolizidine alkaloids (PA), including 7-acetylintermedine, 7-acetyllycopsamine, echimidine, intermedine, lasiocarpine, lycopsamine, myoscorpine, symlandine, symphytine, and symviridine. The mechanisms underlying comfrey-induced genotoxicity and carcinogenicity are still not fully understood. The available evidence suggests that the active metabolites of PA in comfrey interact with DNA in liver endothelial cells and hepatocytes, resulting in DNA damage, mutation induction, and cancer development. Genotoxicities attributed to comfrey and riddelliine (a representative genotoxic PA and a proven rodent mutagen and carcinogen) are discussed in this review. Both of these compounds induced similar profiles of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and similar mutation spectra. Further, the two agents share common mechanisms of drug metabolism and carcinogenesis. Overall, comfrey is mutagenic in liver, and PA contained in comfrey appear to be responsible for comfrey-induced toxicity and tumor induction.

Dietary supplements are consumed by more than 300 million people worldwide, and herbal dietary supplements represent the most rapidly growing portion of this industry. Even though adverse health effects of many herbal dietary supplements have been reported, safety assurances are not being addressed adequately. Toxicological data on the identification of genotoxic and tumorigenic ingredients in many raw herbs are also lacking. Currently, more than 30 herbal dietary supplements and active ingredients have been selected by the National Toxicology Program (NTP) for toxicity and tumorigenicity studies. Due to the complexity of the chemical components present in plant extracts, there are no established methodologies for determining the mechanisms of toxicity (particularly tumorigenicity) induced by herbs, such as Gingko biloba leaf extract (GBE) and other herbal plant extracts. Consequently, the understanding of toxicity of herbal dietary supplements remains limited. We have proposed that application of DNA microarrays could be a highly practical initial approach for revealing biological pathways and networks associated with toxicity induced by herbal dietary supplements and the generation of hypotheses to address likely mechanisms. The changes in expression of subsets of genes of interest, such as the modulation of drug metabolizing genes, can be analyzed after treatment with an herbal dietary supplement. Although levels of gene expression do not represent fully the levels of protein activities, we propose that subsequent biochemical and genomic experiments based on these initial observations will enable elucidation of the mechanisms leading to toxicity, including tumorigenicity. This review summarizes the current practices of microarray analysis of gene expressions in animals treated with herbal dietary supplements and discusses perspectives for the proposed strategy.

Since the U.S. Congress passed the Dietary Supplement Health and Education Act (DSHEA) in 1994, use of herbal products has been growing rapidly worldwide. To ensure consumer health protection, the quality and safety of herbal plants, particularly those used for dietary supplement preparations, must be determined. To date, toxicological data on the identification of genotoxic and tumorigenic ingredients in many raw herbs and their mechanisms of action are lacking. Thus, identification of carcinogenic components in herbal plants is timely and important. In this review, the issues of quality control and safety evaluation of raw herbs and herbal dietary supplements are discussed. Two examples of tumorigenicity and mechanism of tumor induction are discussed: aristolochic acid and riddelliine, both of which have been detected in Chinese herbal plants. It is proposed that an organized effort with international participation on cancer risk assessment should be actively pursued so that the safety of commercial herbal plants and herbal dietary supplements can be ensured.

Nanotechnology has gained a great deal of public interest because of the needs and applications of nanomaterials in many areas of human endeavors including industry, agriculture, business, medicine, and public health. Environmental exposure to nanomaterials is inevitable as nanomaterials become part of our daily life, and, as a result, nanotoxicity research is gaining attention. This review presents a summary of recent research efforts on fate, behavior, and toxicity of different classes of nanomaterials in the environment. A critical evaluation of challenges and future needs for the safe environmental nanotechnology are discussed.

The combination of UVA light and 1-aminopyrene, 1-hydroxypyrene, 1-hydroxybenzo[ a ]pyrene, 3-aminofluoranthene, 6-aminochrysene, or 5-, 6-, and 7-methylbenz[ a ]anthracenes causes DNA single-strand cleavage. 1-Hydroxypyrene, 1-hydroxybenzo[ a ]pyrene, and 5-methylbenz[ a ]anthracene have been shown to cause DNA cleavage, at least partially, by generating singlet oxygen. Therefore, the presence of histidine, a singlet oxygen quencher, should inhibit the DNA photocleavage. However, the presence of 50 mM histidine greatly enhances the DNA photocleavage caused by these compounds. This effect is due to the inhibition of the photodegradation of the PAH compounds. Therefore, care must be taken when interpreting the singlet oxygen quenching data by histidine. Histidine may coexist with PAHs that have entered the body. The presence of histidine can alter the photochemical reaction and, possibly, the phototoxicity mechanism of the PAHs.

Photolysis products of 1-hydroxypyrene (1-HP) were identified by liquid chromatography coupled with mass spectrometry (LC/MS/MS). It was found that the major photoproducts of 1-HP are 1,6-, 1,8-, and one unidentified pyrene quinone and one pyrene quinone dimer based on their HPLC chromatogram and mass spectral data. The photolysis of 1-HP was conducted with pure water, natural river water, and pure water containing commercial humic substances. It was found that the photolysis rate of 1-HP can be inhibited by humic substances, depending on their type and concentration.

UVA light-induced DNA single-strand cleavage by 1-hydroxy, 3-hydroxy, 7-hydroxy, and 9-hydroxybenzo[ a ]pyrenes (OH-B a Ps) and 6-acetoxybenzo[ a ]pyrene (6-OAc-B a P) was studied. Under experimental conditions, the concentrations of 1-OH, 3-OH, 7-OH, and 9-OH-B a Ps and 6-OAc-B a P needed to cause 25% of the supercoiled form I plasmid DNA to become relaxed form II DNA were found to be 0.6, 2.5, 1.0, 1.3, and 1.1 w M, respectively. These concentrations are all smaller than that of B a P, which was 6 w M. These results indicate that on photoirradiation, OH-B a Ps are more cytotoxic and/or genotoxic than their parent compound, B a P. Mechanistic studies reveal that singlet oxygen and superoxide free radicals are involved in causing DNA cleavage.

Dibenz[ a,h ]anthracene (DB[ a,h ]A) and 7-nitrodibenz[ a,h ]anthracene (7-NDB[ a,h ]A) induced liver tumors when administered to neonatal B6C3F 1 mice. For protooncogene analysis, RNA was isolated from each of the liver tumors from treated mice and reverse-transcribed into cDNA. Portions of the K- and H- ras protein coding sequences were then amplified and analyzed for DNA sequence alterations. DB[ a,h ]A-induced liver tumors had a 100% (23/23) frequency of ras -protooncogene mutation, with 83% (19/23) occurring at the first base of K- ras codon 13 and resulting in G GC M C GC transversion; the remaining 17% (4/23) of the mutations were located at the second base of H- ras codon 61. In contrast, only four of nine (44%) of 7-NDB[ a,h ]A-induced liver tumors had ras -protooncogene mutations, with two each at K- ras codon 13 and H- ras codon 61. Combined with previous observations, the results indicate that the nitro substituent perpendicular to the aromatic moiety alters the chemical-induced protooncogene ...

Daily PM2.5, PM2.5–10 and TSP have been collected by Universal and PS‐1 sampler simultaneously at a site within Taichung between February and March 1999. The filters were analyzed by atomic absorption spectrophotometry for the elemental analysis of Ca, Fe, Mn, Pb, Cu, Zn and Cr. In general, the concentration of these metallic elements are higher in fine particles than in coarse particles. On average, PM10 accounted for 67% of the TSP at daytime, while at nighttime PM10 accounted for only 44% of the TSP. For PM2.5, PM2.5–10 and TSP concentrations, there were no significant differences between day and night period. The averaged concentrations of metallic elements in PM2.5 at daytime were all higher than that at nighttime. Ca, Fe and Zn have large and variable PM2.5 concentrations at both daytime and nighttime. For the daytime Zn and Pb account for the largest portion of the heavy metal elements. For the nighttime, Zn and Cr make the largest portion of the heavy metal elements. The concentrations of Mn were ...

Stereoselective metabolism of anthracene, 9-methylanthracene (9-M-A), 9, 10-dimethylanthracene (9, 10-DMA), 9-chloroanthracene (9-Cl-A), and 9-nitroanthracene (9-nitro-A) by liver microsomes of neonatal (15-day old) male B6C3F1 mice in the presence of a NADPH regenerating system was conducted. After incubation, reversed-phase HPLC separation, and spectral analyses the following were identified: anthracene trans-1,2-dihydrodiol, 9-M-A trans-1,2- and -3,4-dihydrodiol, 9,10-DMA trans-1,2-dihydrodiol, 9-Cl-A trans-1,2- and -3,4-dihydrodiol, and 9-nitro-A trans-1,2- and -3,4-dihydrodiol. Circular dichroism (CD) spectral analysis indicated the major enantiomers of the anthracene, 9-M-A, 9,10-DMA, and 9-Cl-A trans-dihydrodiols all had R,R absolute configurations. These results indicate that these compounds are metabolized in a stereoselective manner by liver microsomes of neonatal male B6C3F1 mice.

N-(Deoxyguanosin-8-yl)-2-aminopyrene and N-(deoxyadenosin-8-yl)-2-aminopyrene were formed from metabolism of 2-nitropyrene (2-NP) in vitro and in vivo. The effects of dietary restriction (DR) and age on the formation of these DNA adducts were studied. In the presence of calf thymus DNA, [G-3H]2-NP was metabolized by liver microsomes of 5-, 9-, and 12-month old male B6C3F1 mice fed ad libitum (AL microsomes) or by liver microsomes of 5-, 9-, and 12-month old male B6C3F1 mice fed a restricted diet (DR microsomes). In all cases, both adducts were detected. The total quantities formed from 5-, 9-, and 12-month AL microsomes, and 5-, 9-, and 12-month DR microsomes were 5.58±1.78, 8.79±2.32, 3.57±0.34, 1.63±0.40, 5.46±0.21, and 4.15±0.94 pmol 2-NP/mg DNA, respectively. These results suggest the effect of DR on DNA adduct formation may be age dependent. However, the ratio of dG/dA adduct formation was similar in all cases and was independent of age and caloric intake of the mice used for the microsomal ...

Benz[a]anthracene (BA) has been reported to be a noncarcinogen or a borderline weak carcinogen in several chronic bioassay systems. For comparison, we determined its tumorigenicity in the neonatal male B6C3F1 mouse. Mice were administered i.p. injections (1600 nmol total dose per mouse) within 24 hrs of birth and at 8 and 15 days of age. BA induced hepatocellular adenomas and carcinomas in 75 and 25% of the mice, respectively, while the solvent control (DMSO) induced 8 and 4%, respectively. Analysis by RT-PCR indicated that 86% (12/14) of BA-induced liver tumors had activated ras protooncogenes, 11 with a pattern of GGC→CGC at K-ras codon 13. Our results clearly demonstrate that BA is a potent tumorigen in the neonatal B6C3F1 mouse and induces a unique type of K-ras-oncogene activation.

(1999). Halogenated‐polycyclic aromatic hydrocarbons: A class of Genotoxic environmental pollutants. Journal of Environmental Science and Health, Part C: Vol. 17, No. 2, pp. 71-109.

Chlorinated PAHs have been identified as a class of potent genotoxic environmental contaminants. Dibenzo[a,l]pyrene (DB[a,l]P) is a potent tumorigenic environmental pollutant. In this paper, we report the synthesis, rat liver microsomal metabolism, and determination of the effect of the chloro substituent on metabolism of DB[a,l]P,2-Cl-DB[a,l]P, and 10-Cl-DB[a,l]P. The metabolism of DB[a,l]P, 2-Cl-DB[a,l]P, and 10-Cl-DB[a,l]P produced trans-8,9-dihydrodiol, trans-11,12-dihydrodiol, and 7-hydroxyl metabolites as major products. The trans-dihydrodiols of DB[a,l]P and 2-Cl-DB[a,l]P preferentially adopt a quasidiequatorial conformation, and the 10-Cl-DB[a,l]P trans-dihydrodiols adopt a quasidiaxial conformation. Based on the yield and conformation of trans-11,12-dihydrodiol, we predict the biological activities of these compounds are: DB[a,l]P > 2-Cl-DB[a,l]P ≫ 10-Cl-DB[a,l]P.

We have characterized the DNA adducts of a series of nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) formed under anaerobic conditions in vitro. Although the DNA adducts of nitro-PAHs formed through enzymatic nitroreduction are generally the C8-deoxyguanosyl adducts, nitroreduction of 1-nitrobenzo[a]pyrene (1-nitro-BaP), 3-nitro-BaP, and two derivatives in the presence of calf thymus DNA resulted in the N 2-deoxyguanosyl adducts with the deoxyguanosyl moiety remote from the reaction site. Two DNA adducts of this type were also formed from 1-nitropyrene as minor products. These DNA adducts were formed from anaerobic incubation with rat and mouse liver microsomes and cytosols in the presence of calf thymus DNA. Our results suggest that biological formation of this type of DNA adduct is independent of the enzymatic system, but dependent on the geometric structure and/or electronic features of the nitro-PAH molecules.

Pure cultures of anaerobic intestinal bacteria and mixed fecal microflora from human, rat, mouse, and pig were screened for the ability to metabolize 7‐nitrobenz[a]anthracene (7‐NO2BA). Based on analysis by high‐performance liquid chromatography (HPLC) and by ultraviolet (UV), mass, and nuclear magnetic resonance (NMR) spectral techniques, the compounds were identified as 7‐aminobenz[a]anthracene (7‐NH2BA) and benz[a]anthracene 7, 12‐dione (dione). Identification of 7‐NH2BA as a metabolite of 7‐NO2BA indicates that the anaerobic intestinal bacteria are capable of reducing 7‐NO2BA to potentially bioactive intermediates. The reductive capacities of the mixed intestinal microflora were generally greater than those of pure cultures. Thus, metabolism of 7‐NO2BA in the intestinal tract may 6e underestimated if pure cultures are used as the sole method for evaluating the potential hazard.

7-Nitrodibenz[a,h]anthracene (7-nitro-DB[a,h]A) has been found to be less hepatocarcinogenic than its parent compound, dibenz[a,h]anthracene (DB[a,h]A). To examine the effect of the nitro functional group on metabolism, metabolism of 7-nitro-DB[a,h]A by rat liver microsomes was studied. The metabolites were purified by reversed-phase high pressure liquid chromatography and characterized by analysis of their UV-visible, mass and NMR spectral data. Four metabolites were identified, 7-nitro-DB[a,h]A trans-1,2-dihydrodiol, 7-nitro-DB[a,h]A trans-3,4-dihydrodiol, 2-hydroxy-7-nitro-DB[a,h]A, and 4-hydroxy-7-nitro-DB[a,h]A. The uniqueness of these metabolites is that they are all formed from metabolism at the 1,2,3,4-benzo ring of the 7-nitro-DB[a,h]A molecule. No metabolites derived from the other regions of 7-nitro-DB[a,h]A are found. Comparison of the metabolism results of 7-nitro-DB[a,h]A and DB[a,h]A indicates that the nitro substituent significantly affects the regioselectivity of the metabolism.

Effect of caloric restriction (CR) on metabolism of 7-fluorobenz-[a]anthracene (7-F-BA), 7-chlorobenz[a]anthracene (7-Cl-BA), 7-bromo-benz[a]anthracene (7-Br-BA), and 7-nitrobenz[a]anthracene (7-nitro-BA) by mouse liver microsomes was studied. The results indicate that CR can affect metabolism rate, modulate the regioselectivity and stereoselectivity of the cytochrome P-450 metabolizing enzymes, and lower the yield of the proximate mutagenic metabolites. These findings indicate that CR may in part modulate chemical carcinogenesis by altering the metabolic activation.

In vivo studies of the metabolic activation of 2-nitrofluoranthene (2-NFA) were conducted by incubating Salmonella typhimurium TA98 suspension cultures with 2-NFA (10 or 20μM) for 4 hr. The DNA was isolated and the resulting DNA adducts were analyzed by HPLC and 32P-postlabeling. In addition, neonatal mice were administered a total dose of 400 nmol 2-NFA in 35 μ1 dimethylsulfoxide (DMSO) by i.p. injection on 1, 8, and 15 days after birth with 1/7, 2/7, and 4/7, respectively, of the total dose. Livers were removed from the mice 24 hr, 48 hr, and 7 days after the last dose and the DNA isolated for 32P-postlabeling adduct analysis. N−(Deoxyguanosin-8-yl)-2-aminofluoranthene and a second adduct were identified in the DNA from the Salmonella suspensions and one of these adducts was found in the neonatal mice. These results suggest that 2-NFA is metabolically activated to N−hydroxy-2-aminofluoranthene via nitroreduction and that the resulting DNA adduct is responsible for the mutagenic activities of 2-NFA.

2-Nitrobenzo[a]pyrene (2-nitro-BaP) induced 100% liver tumor incidence in the neonatal mouse tumorigenicity assay and exhibited the highest mutagenicity among the 1-, 2-, 3-, and 6-nitro-BaP when tested in Salmonella typhimurium TA98 and TA100. To determine the metabolic activation pathways leading to tumor initiation and mutation induction, we have studied the aerobic metabolism of 2-nitro-BaP by Sprague-Dawley rat and B6C3F1 mouse liver microsomes. Metabolites were isolated by HPLC and characterized by spectral analyses, including UV-visible absorption, mass and proton NMR spectroscopy. With both rat and mouse liver microsomes, 2-nitro-BaP trans-9,10-dihydrodiol and 2-nitro-BaP trans-7,8-dihydrodiol were formed as the predominant metabolites, and 2-nitro-BaP 7,8,9,10-tetrahydrotetrol was produced in trace quantities. 2-Nitro-BaP and its two dihydrodiol metabolites were assayed in Salmonella typhimurium tester strain TA98. 2-Nitro-BaP trans-7,8-dihydrodiol, in the presence of S9, was the most mu...

We have studied in vitro metabolism, DNA adduct formation, mutagenicity, and tumorigenicity of a series of nitro−polycyclic aromatic hydrocarbons. The emphasis has been focused on the isomeric nitrobenzo−[a]pyrenes and related compounds. We have previously shown that in vitro there are multiple pathways for the mutagenic activation of 1− and 3−nitro−BaP. In this paper we report that DNA adducts formed from nitroreduction of 1− and 3−nitro−BaP involve a long range migration. DNA adducts from the ultimate metabolites, the bay−region trans−7,8−diol−anti−9, 10−epoxides of 1− and 3−nitro−BaPs have also been obtained. We have also found that a nitro−PAH with its nitro functional group perpendicular to the aromatic moiety exhibits less tumorigenicity than the parent PAH.

Aerobic metabolism of 9-nitroanthracene, an environmental contaminant, by liver microsomes of uninduced rats (control-microsomes) and rats pretreated with 3-methylcholanthrene and phenobarbital (MC-and PB-microsomes) in the presence of the epoxide hydrolase inhibitor, 3,3,3-trichloropropylene 1,2-oxide (TCPO), was studied. 9-Nitroanthracene 1,2- and 3,4-epoxide were isolated by consecutive reversed- and normal-phase HPLC. The structural identity of these metabolites was established by analysis of their mass spectral and high resolution proton NMR spectral data. Unlike anthracene 1,2-epoxide, which is extremely unstable and facilely undergoes nonenzymatic rearrangement to hydroxyanthracenes, 9-nitroanthracene 1,2- and 3,4-epoxides were very stable in storage and during NMR spectral measurements. In all three enzymatic systems, 9-nitroanthracene 3,4-epoxide was formed in a higher yield than the 1,2-epoxide isomer, but the ratio of these two metabolites varied. Analysis of their circular dichroism s...

Rat liver microsomal metabolism of 8‐fluorobenzo[a]pyrene (8‐fluoro‐BaP) generated 3‐hydroxy‐8‐fluora‐BaP, 8‐fluoro‐BaP trans‐4,5‐dihydrodiol, and 8‐fluoro‐BaP, 3,6‐quinone as major products. A minor metabolite of 8‐fluoro‐BaP was tentatively assigned as 8‐fluoro‐BaP 9,10‐dihydrodiol. Metabolism of 9‐fluorobenzo[a] pyrene (9‐fluoro‐BaP) gave 3‐hydroxy‐9‐fluoro‐BaP, 9‐fluoro‐BaP trans‐4,5‐dihydrodiol, 9‐fluoro‐BaP trans‐7,8‐dihydrodiol, and 9‐fluoro‐BaP 3,6‐quinone. All three dihydrodiol metabolites were optically active. Comparison of the circular dichroism spectra of BaP 4R,5R‐dihydrodiol, 6‐bromo‐BaP 7R,8R‐dihydrodiol, and 6‐fluoro‐BaP 7R,8R‐dihydrodiol with those of the respective dihydrodiol metabolites allowed assignments of an R,R absolute configuration to the major enantiomers of the three dihydrodiol metabolites.

(1981). SYNTHESIS OF BENZO[a]PYRENE-12-OL. Organic Preparations and Procedures International: Vol. 13, No. 2, pp. 152-155.

The fungal metabolism of the potent mutagenic and carcinogenic nitropolycyclic aromatic hydrocarbon (nitro-PAH) 6-nitrobenzo[a]pyrene (6-NO2-BaP) was investigated. Cunninghamella elegans was incubated with 6-NO2-BaP for periods ranging between 1 and 7 d, and the metabolites formed were separated by high-performance liquid chromatography and identified by their UV-visible absorption, mass, and 1H nuclear magnetic resonance spectra. The results of our study indicate that C. elegans metabolized 6-NO2-BaP to glucoside and sulfate conjugates of 1- and 3-hydroxy 6-NO2-BaP and suggests that glycosylation and sulfation reactions may represent detoxification pathways in the fungal metabolism of nitro-PAHs. Experiments using [G3H]-6-NO2-BaP indicated that C. elegans metabolized 62% of 6-NO2-BaP within 168 h. Our data also indicated that the nitro group at the C-6 position of benzo[a]pyrene blocked metabolism at the regions peri to the nitro substituent (C-7, C-8 positions) and enhanced metabolism at the C-1 and C-3 positions. The ability of the fungus C. elegans to metabolize 6-NO2-BaP to biologically inactive compounds may have practical applications in the detoxification of nitro-PAH-contaminated wastes.

(1984). SYNTHESIS OF 6-SUBSTITUTED 3-DEUTEROBENZO[A]PYRENE. Organic Preparations and Procedures International: Vol. 16, No. 3-4, pp. 279-285.

(1982). A MODIFIED APPROACH IN THE SYNTHESIS OF 5- AND 6-METHYLBENZ[a]ANTHRACENES. Organic Preparations and Procedures International: Vol. 14, No. 3, pp. 169-175.

The compounds 1-, 3-, and 6-nitrobenzo[a]pyrene (nitro-BaP) are environmental pollutants and have been shown to be potent bacterial mutagens. The anaerobic metabolism of these isomeric nitro-BaPs was investigated by the incubation of rat intestinal microflora with each isomer for 48 h. Aliquots were removed at several time intervals, extracted, fractionated by high-pressure liquid chromatography (HPLC), and the radioactivity determined. Metabolites were identified by comparison of their chromatographic, ultraviolet-visible absorption, and mass spectral properties with those of authentic standards. The order of the extent of nitroreduction for these isomers was 3-nitro-BaP greater than 6-nitro-BaP greater than 1-nitro-BaP. After 48 h of exposure, 84% of the added 3-nitro-BaP was present as 3-amino-BaP, 51% of the 6-nitro-BaP was metabolized to 6-amino-BaP, and 1-nitro-BaP was reduced to 1-amino-BaP (13%) and 1-nitro-BaP (4%). The order of the extent of microbial nitroreduction for these nitro-BaP isomers is different from the predictions based on electronic and steric hindrance effects. These results suggest that intestinal microflora nitroreductases exhibit a markedly high degree of substrate specificity toward nitro-BaPs that affects the extent of nitroreduction.

(1982). SYNTHESIS OF 7-HYDROXYBENZO[a]PYRENE. Organic Preparations and Procedures International: Vol. 14, No. 6, pp. 414-417.

The direct resolution of trans and cis bay region dihydrodiol and tetrahydrodiol enantiomers of benz[a]anthracene and benzo[a]-pyrene, and trans and cis K-region dihydrodiol enantiomers of benz[a]anthracene, 4-methylbenz[a]anthracene, 7-methylbenz[a]anthracene, 7,12-dimethylbenz[a]anthracene, and 3-methylcholanthrene was evaluated by high-performance liquid chromatography using commercially available columns packed with (R)-N-(3,5-dinitrobenzoyl)phenylglycine and (S)-N-(3,5-dinitrobenzoyl)leucine either ionically or covalently bonded to γ-aminopropylsilanized silica. Except benz[a]anthracene trans-5,6-dihydrodiol, the diol enantiomers of other hydrocarbons were all resolved by at least one of the four chiral stationary phases tested. The absolute configurations of enantiomeric diols, whose hydroxyl groups' conformations are restricted due to steric factors, have been established by the exciton chirality circular dichroism method. Based on the experimental results, the mechanisms of some chiral in...