International Journal of Molecular Sciences

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Open AccessEditorial

A Message from the Director

by Sidney A. McNairy

Int. J. Mol. Sci. 2002, 3(9), 934-936; https://doi.org/10.3390/i3090934 - 30 Sep 2002

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Abstract

The National Institutes of Health (NIH), located in Bethesda, Maryland, a suburb of Washington, D.C., is one of the agencies of the Public Health Services that, in turn, is part of the U.S. Department of Health and Human Services.[...] Full article

(This article belongs to the Special Issue Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis. Part I)

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Open AccessEditorial

Special Issue on Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis

by Paul B. Tchounwou and Hongtao Yu

Int. J. Mol. Sci. 2002, 3(9), 931-933; https://doi.org/10.3390/i3090931 - 30 Sep 2002

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Abstract

Recent development in biomedical research and clinical sciences has lead to a significant decrease in disease morbidity and mortality, as well as the improvement of quality of life in the United States and around the world.[...] Full article

(This article belongs to the Special Issue Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis. Part I)

Research

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Open AccessArticle

Detection of Riddelliine-Derived DNA Adducts in Blood of Rats Fed Riddelliine

by Jian Yan, Jasyl Nichols, Ya-Cheng Yang, Peter P. Fu and Ming W. Chou

Int. J. Mol. Sci. 2002, 3(9), 1019-1026; https://doi.org/10.3390/i3091019 - 30 Sep 2002

Cited by 15 | Viewed by 9281

Abstract

We have previously shown that riddelliine, a naturally occurring genotoxic pyrrolizidine alkaloid, induces liver tumors in rats and mice through a genotoxic mechanism mediated by the formation of a set of eight 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5Hpyrrolizine ( DHP)-derived DNA adducts. In this study we report the [...] Read more.

We have previously shown that riddelliine, a naturally occurring genotoxic pyrrolizidine alkaloid, induces liver tumors in rats and mice through a genotoxic mechanism mediated by the formation of a set of eight 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5Hpyrrolizine ( DHP)-derived DNA adducts. In this study we report the formation of these DHP-derived DNA adducts in blood DNA of rats fed riddelliine. In an adduct formation and removal experiment, male and female F344 rats (8 weeks of age) were administered riddelliine by gavage at a single dose of 10.0 mg/kg body weight in 0.1 M phosphate buffer. At 8, 24, 48, and 168 hrs after dosing, the levels of DHP-derived DNA adduct in blood and liver were determined by ³²P-postlabeling/HPLC. Maximum DNA adduct formation occurred at 48 hr after treatment. From 48 to 168 hours, the adduct levels in female rat blood were 4-fold greater than those in male rats. In a dose response experiment, female rats were gavaged 0.1 and 1.0 mg/kg doses of riddelliine for three consecutive days and the DHPderived DNA adducts in blood DNA were assayed. The levels of the DHP-derived DNA adducts in blood of rats receiving 0.1 and 1.0 mg/kg doses were 12.9 and 51.8 adducts/10⁷nucleotides. These results suggest that: (i) leucocyte DNA can bind with DHP to form a set of DHP-derived DNA adducts generated in liver; (ii) DHP-derived DNA adducts in blood can serve as a potential non-invasive biomarkers for assessing the exposure to riddelliine. Full article

(This article belongs to the Special Issue Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis. Part I)

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Open AccessArticle

In Vitro Metabolism of Dibenzo[a,l]pyrene, 2-Chlorodibenzo [a,l]pyrene and 10-Chlorodibenzo[a,l]pyrene - Effects of Chloro Substitution

by Yuh-Shen Wu, Guor-Cheng Fang, Joanna Moody, Linda S. Von Tungeln, Peter P. Fu, Huey-Min Hwang and Hongtao Yu

Int. J. Mol. Sci. 2002, 3(9), 1008-1018; https://doi.org/10.3390/i3091008 - 30 Sep 2002

Cited by 2 | Viewed by 8429

Abstract

Stereoselective metabolism of dibenzo[a,l]pyrene (DB[a,l]P), 2-chlorodibenzo[a,l]pyrene (2-Cl-DB[a,l]P) and 10-chlorodibenzo[a,l]pyrene (10-Cl-DB[a,l]P) by rat liver microsomes was studied and effects of the chloro substituent on the metabolism were determined. All three compounds produced trans-8,9-dihydrodiol, trans-11,12-dihydrodiol, and the 7-hydroxyl derivative as major metabolic products and several [...] Read more.

Stereoselective metabolism of dibenzo[a,l]pyrene (DB[a,l]P), 2-chlorodibenzo[a,l]pyrene (2-Cl-DB[a,l]P) and 10-chlorodibenzo[a,l]pyrene (10-Cl-DB[a,l]P) by rat liver microsomes was studied and effects of the chloro substituent on the metabolism were determined. All three compounds produced trans-8,9-dihydrodiol, trans-11,12-dihydrodiol, and the 7-hydroxyl derivative as major metabolic products and several other phenolic derivatives as minor metabolites. The trans-8,9- and 11,12-dihydrodiols of DB[a,l]P and 2-Cl-DB[a,l]P preferentially adopted a quasidiequatorial conformation, whereas 10-Cl-DB[a,l]P trans-8,9- and 11,12-dihydrodiols preferentially adopted a quasidiaxial conformation. The yields of the trans-11,12-dihydrodiol metabolites are: DB[a,l]P trans-11,12-dihydrodiol > 2-Cl-DB[a,l]P trans-11,12-dihydrodiol >> 10-Cl-DB[a,l]P trans-11,12-dihydrodiol. Circular dichroism (CD) spectral analysis indicates that the trans-8,9-dihydrodiol and trans-11,12-dihydrodiol metabolites from DB[a,l]P, 2-Cl-DB[a,l]P, and 10-Cl-DB[a,l]P are optically active. Furthermore, the major enantiomeric DB[a,l]P trans-11,12-dihydrodiol and 2-Cl-DB[a,l]P trans-11,12-dihydrodiol had R,R absolute configuration. Based on the fact that DB[a,l]P trans-11,12-dihydrodiol is the proximate tumorigenic metabolite of DB[a,l]P, our results suggest that DB[a,l]P exhibits the highest tumorigenic potency followed by 2-Cl-DB[a,l]P, and 10-Cl-DB[a,l]P exhibits the lowest tumorigenicity. Full article

(This article belongs to the Special Issue Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis. Part I)

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Open AccessArticle

Transcriptional Activation of Stress Genes and Cytotoxicity in Human Liver Carcinoma (HepG₂) Cells Exposed to Pentachlorophenol

by Waneene C. Dorsey, Paul B. Tchounwou, Ali B. Ishaque and Elaine Shen

Int. J. Mol. Sci. 2002, 3(9), 992-1007; https://doi.org/10.3390/i3090992 - 30 Sep 2002

Cited by 8 | Viewed by 10248

Abstract

Pentachlorophenol (PCP) is a biocidal chemical with several industrial, agricultural, and domestic applications. There is accumulating evidence indicating that PCP is highly toxic to humans, with major target organs including the lung, liver, kidneys, heart, and brain. Little is known regarding the molecular [...] Read more.

Pentachlorophenol (PCP) is a biocidal chemical with several industrial, agricultural, and domestic applications. There is accumulating evidence indicating that PCP is highly toxic to humans, with major target organs including the lung, liver, kidneys, heart, and brain. Little is known regarding the molecular basis by which PCP induces toxicity, mutagenesis, and carcinogenesis. Therefore, this research was designed to assess the cellular and molecular responses of HepG2 cells following exposure to PCP. The cytotoxicity experiment yielded a LD50 value of 23.4 + 9.7 μg PCP/mL upon 48 hrs of exposure, indicating that PCP is acutely toxic. A dose-response relationship was recorded with respect to gene induction. For example, fold inductions of CYP1A1 were 1.0 + 0.0, 1.0 + 0.0, 1.3 + 0.5, 6.3 + 4.3, and 22.5 + 3.5 for 0, 6.2, 12.5, 25, and 50 μg PCP/mL, respectively. Overall, five out of the thirteen recombinant cell lines tested showed inductions to statistically significant levels (p < 0.05). At 50 μg PCP/mL, the average fold inductions were 22.5 + 3.5, 52.8 + 2.5, 8.4 + 1.9, 6.16 + 2.4, and 12.5 + 6.8, for CYP1A1, XRE, HMTIIA, c-fos, and GADD153, respectively. These results indicate the potential of PCP to undergo Phase I biotransformation in the liver (CYP1A1, XRE), to cause cell proliferation (c-fos), growth arrest and DNA damage (GADD153), and to influence the toxicokinetics of metal ions (HMTIIA). Marginal inductions were recorded for HSP70, CRE, RARE, GADD45, and GRP78. Within the dose range (0-100 μg/mL) tested, no significant inductions (p < 0.05) were observed for GSTYa, NFkBRE, and p53RE. Full article

(This article belongs to the Special Issue Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis. Part I)

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Open AccessArticle

Effect of Turmerin on Endothelial Denudation by Air Drying

by H. H. P. Cohly, C. Hammet, M. F. Angel, V. Kanji, A. Taylor, H. Benghuzzi and A. K. Markov

Int. J. Mol. Sci. 2002, 3(9), 985-991; https://doi.org/10.3390/i3090985 - 30 Sep 2002

Cited by 2 | Viewed by 9398

Abstract

The objective of this study is to determine if arterial endothelial injury can be attenuated by local application of 80 μg/ml turmerin at the site of injury and by oral administration of the same dose. Anesthetized Lewis rats (n =12) weighing 200 ± [...] Read more.

The objective of this study is to determine if arterial endothelial injury can be attenuated by local application of 80 μg/ml turmerin at the site of injury and by oral administration of the same dose. Anesthetized Lewis rats (n =12) weighing 200 ± 4.0 gms randomly were assigned to two groups. After 5 min of air drying a segment of right carotid artery, six rats were treated locally 80μg/ml with turmerin and the rest were treated with 0.9% NaCl. Turmerin was then administered by gavage (80 μg) every 24 hrs for 14 days. Animals were sacrificed on day 14 and the carotid artery removed from the injured site for histological analysis and serum collected for lipid peroxidation analysis by measuring malondialdehyde (MDA) and conjugated dienes. This study showed no proliferation in the intima of one rat out of six rats treated with turmerin while there was significant variation between the treated rats and the controls. MDA for control was 0.593±0.02 nanomoles/ml while turmerin was 0.187±0.04 (p≤0.01); conjugated diene for control was 0.402±0.03 nanomoles/ml while turmerin was 0.212±0.04 nanomoles/ml (p ≤0.05). Although there was significant reduction in serum peroxidation activity, the histological findings indicate that attenuation of carotid artery injury may involve other factors than decreased lipid peroxidation. Full article

(This article belongs to the Special Issue Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis. Part I)

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Mercury Induces Cytotoxicity and Transcriptionally Activates Stress Genes in Human Liver Carcinoma (HepG₂) Cells

by Dwayne J. Sutton, Paul B. Tchounwou, Nanuli Ninashvili and Elaine Shen

Int. J. Mol. Sci. 2002, 3(9), 965-984; https://doi.org/10.3390/i3090965 - 30 Sep 2002

Cited by 43 | Viewed by 14350

Abstract

Mercury is a non-essential element that exhibits a high degree of toxicity to humans and animals. Exposure to mercury has been associated with a significant number of adverse health effects including: cardiovascular disease, anemia, developmental abnormalities, neurobehavioral disorders, kidney and liver damage, and [...] Read more.

Mercury is a non-essential element that exhibits a high degree of toxicity to humans and animals. Exposure to mercury has been associated with a significant number of adverse health effects including: cardiovascular disease, anemia, developmental abnormalities, neurobehavioral disorders, kidney and liver damage, and cancer in some cases. In several studies, the toxicity of mercury has been attributed to its high affinity to protein-containing sulfhydryl groups. However, little is known regarding the molecular mechanisms by which mercury exerts its toxicity, mutagenesis, and carcinogenesis. This research was therefore designed to assess the cellular and molecular responses of human liver carcinoma cells following exposure to mercury. Cytotoxicity was evaluated using the MTT-assay for cell viability, while the gene profile assay was performed to measure the transcriptional activation of stress genes in thirteen different recombinant cell lines generated from HepG2 cells. Cytotoxicity experiment yielded a LD50 value of 3.5 ± 0.6 μg/mL upon 48 hours of exposure, indicating that mercury is highly toxic. A dose response relationship was recorded with respect to both cytotoxicity and gene induction. Overall, nine out of the thirteen recombinant cell lines tested showed inductions to statistically significant levels (p < 0.05). At 2.5 μg/mL of mercury, the average fold inductions were 5.2 ± 0.9, 21.4 ± 3.9, 7.0 ± 6.2, 6.8 ± 1.1, 2.7 ± 1.0, 4.5 ± 2.0, 7.5 ± 6.0, 2.2 ± 0.7, and 2.5 ± 0.3, for GSTYa, HMTIIA, c-fos, HSP70, CRE, p53RE, GADD153, GADD45, and GRP78, respectively. These results indicate the potential of mercury to undergo Phase II biotransformation in the liver (GSTYa), and to cause protein damage (HMTIIA, HSP70, and GRP78), cell proliferation (c-fos), metabolic perturbation (CRE), growth arrest and DNA damage (GADD153, GADD45), and apoptosis (p53RE). No significant inductions (p > 0.05) were observed for CYP1A1, XRE, NFkBRE, and RARE. Full article

(This article belongs to the Special Issue Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis. Part I)

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Open AccessArticle

Genotoxic Pyrrolizidine Alkaloids — Mechanisms Leading to DNA Adduct Formation and Tumorigenicity

by Peter P. Fu, Qingsu Xia, Ge Lin and Ming W. Chou

Int. J. Mol. Sci. 2002, 3(9), 948-964; https://doi.org/10.3390/i3090948 - 30 Sep 2002

Cited by 77 | Viewed by 12922

Abstract

Plants that contain pyrrolizidine alkaloids are widely distributed in the world. Although pyrrolizidine alkaloids have been shown to be genotoxic and tumorigenic in experimental animals, the mechanisms of actions have not been fully understood. The results of our recent mechanistic studies suggest that [...] Read more.

Plants that contain pyrrolizidine alkaloids are widely distributed in the world. Although pyrrolizidine alkaloids have been shown to be genotoxic and tumorigenic in experimental animals, the mechanisms of actions have not been fully understood. The results of our recent mechanistic studies suggest that pyrrolizidine alkaloids induce tumors via a genotoxic mechanism mediated by 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5Hpyrrolizine (DHP)-derived DNA adduct formation. This mechanism may be general to most carcinogenic pyrrolizidine alkaloids, including the retronecine-, heliotridine-, and otonecinetype pyrrolizidine alkaloids. It is hypothesized that these DHP-derived DNA adducts are potential biomarkers of pyrrolizidine alkaloid tumorigenicity. The mechanisms that involve the formation of DNA cross-linking and endogenous DNA adducts are also discussed. Full article

(This article belongs to the Special Issue Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis. Part I)

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255 KiB

Open AccessArticle

Effect of Organic Solvents and Biologically Relevant Ions on the Light-Induced DNA Cleavage by Pyrene and Its Amino and Hydroxy Derivatives

by Shiming Dong, Shuguang Wang, Gernerique Stewart, Huey-Min Hwang, Peter P. N. Fu and Hongtao Yu

Int. J. Mol. Sci. 2002, 3(9), 937-947; https://doi.org/10.3390/i3090937 - 30 Sep 2002

Cited by 15 | Viewed by 12356

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are a class of carcinogenic compounds that are both naturally and artificially produced. Many PAHs are pro-carcinogens that require metabolic activation. Recently, it has been shown that PAH can induce DNA single strand cleavage and formation of PAH-DNA covalent [...] Read more.

Polycyclic aromatic hydrocarbons (PAHs) are a class of carcinogenic compounds that are both naturally and artificially produced. Many PAHs are pro-carcinogens that require metabolic activation. Recently, it has been shown that PAH can induce DNA single strand cleavage and formation of PAH-DNA covalent adduct upon irradiation with UVA light. The light-induced DNA cleavage parallels phototoxicity in one instance. The DNA photocleavage efficiency depends on the structure of the PAHs. This article reports the effect of both organic solvents and the presence of biologically relevant ions, Na⁺, Mg²⁺, Ca²⁺, K⁺, Fe³⁺, Cu²⁺, Zn⁺², Mn²⁺, and I^-, on the light-induced DNA cleavage by pyrene, 1-hydroxypyrene and 1-aminopyrene. Since both 1-hydroxypyrene (0.6 μM) and 1-aminopyrene (6 μM) dissolve well in the minimum organic solvents used (2% methanol, dimethylsulfoxide, and dimethylformamide), increasing the amount of the organic solvent resulted in the decrease of the amount of DNA single strand cleavage caused by the combination effect of 1-hydroxy or 1-aminopyrene and UVA light. The result with the less watersoluble pyrene shows that increase of the amount of the organic solvent can increase the amount of DNA single strand DNA photocleavage cause by the combination of pyrene and UVA light. Therefore, there are two effects by the organic solvents: (i) to dissolve PAH and (ii) to quench DNA photocleavage. The presence of Fe³⁺ and Zn²⁺ enhances, while the presence of Ca²⁺ and Mn²⁺ inhibits the DNA photocleavage caused by 1-aminopyrene and UVA light. Other metal ions have minimal effect. This means that the effect of ions on DNA photocleavage by PAHs is complex. The presence of KI enhances DNA photocleavage. This indicates that the triplet-excited state of 1-aminopyrene is involved in causing DNA cleavage Full article

(This article belongs to the Special Issue Recent Advances in Environmental Health Research: Health Disparities, Toxicology and Carcinogenesis. Part I)

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