Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: A review

Xue, Wenhao; Warshawsky, David

doi:10.1016/j.taap.2004.11.006

Cited by 767 publications

(492 citation statements)

References 105 publications

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“…The CYP1A subfamily are key enzymes in the metabolic activation of numerous environmental xenobiotics, including many that enter the body via the respiratory system. Metabolic activation by the CYP1A subfamily of enzymes results in the production of highly reactive intermediates that have been shown to damage DNA [39,40]. Thus induction of this enzyme in either the liver or lung may lead to increased tissue damage.…”

Section: Discussionmentioning

confidence: 99%

Regulatory mechanisms to control tissue α-tocopherol

Mustacich

Elias

et al. 2007

Free Radical Biology and Medicine

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To test the hypothesis that hepatic regulation of α-tocopherol metabolism would be sufficient to prevent over-accumulation of α-tocopherol in extrahepatic tissues and that administration of high doses of α-tocopherol would up-regulate extrahepatic xenobiotic pathways, rats received daily subcutaneous injections of either vehicle or 0.5, 1, 2, or 10 mg α-tocopherol/100 g body wt for 9 days. Liver α-tocopherol increased 15-fold in rats given 10 mg α-tocopherol/100 g body weight (mg/ 100 g) compared with controls. Hepatic α-tocopherol metabolites increased with increasing α-tocopherol doses, reaching 40-fold in rats given the highest dose. In rats injected with 10 mg/100 g, lung and duodenum α-tocopherol concentrations increased 3-fold, while α-tocopherol concentrations of other extrahepatic tissues increased 2-fold or less. With the exception of muscle, daily administration of less than 2 mg/100 g) failed to increase α-tocopherol concentrations in extrahepatic tissues. Lung cytochrome P450 3A and 1A levels were unchanged by administration of α-tocopherol at any dose. In contrast, lung P-glycoprotein (MDR-1) levels increased dose dependently and expression of this xenobiotic transport protein was correlated with lung α-tocopherol concentrations (R 2 = 0.88, P < 0.05). Increased lung MDR1 may provide protection from exposure to environmental toxins by increasing alveolar space α-tocopherol.

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Section: Discussionmentioning

confidence: 99%

Regulatory mechanisms to control tissue α-tocopherol

Mustacich

Elias

et al. 2007

Free Radical Biology and Medicine

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“…The environmental chemical pollutant benzo [a]pyrene is metabolically activated to form highly reactive intermediates that can subsequently react with DNA, yielding carcinogen-DNA adducts [72,73]. These lesions can produce mutations on replication in vitro and in vivo [74][75][76].…”

Section: Box 3 Benzo[a]pyrene-derived Dna Lesionsmentioning

confidence: 99%

Lesion processing: high-fidelity versus lesion-bypass DNA polymerases

Broyde¹,

Wang²,

Rechkoblit³

et al. 2008

Trends in Biochemical Sciences

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When a high-fidelity DNA polymerase encounters certain DNA-damage sites, its progress can be stalled and one or more lesion-bypass polymerases are recruited to transit the lesion. Here, we consider two representative types of lesions: (i) 7,8-dihydro-8-oxogua-nine (8-oxoG), a small, highly prevalent lesion caused by oxidative damage; and (ii) bulky lesions derived from the environmental pre-carcinogen benzo [a]pyrene, in the high-fidelity DNA polymerase Bacillus fragment (BF) from Bacillus stearothermophilus and in the lesion-bypass DNA polymerase IV (Dpo4) from Sulfolobus solfataricus. The tight fit of the BF polymerase around the nascent base pair contrasts with the more spacious, solvent-exposed active site of Dpo4, and these differences in architecture result in distinctions in their respective functions: one-step versus stepwise polymerase translocation, mutagenic versus accurate bypass of 8-oxoG, and polymerase stalling versus mutagenic bypass at bulky benzo[a]pyrene-derived lesions. Lesions and DNA polymerasesUntil 1999, it was widely understood that bacteria have three DNA polymerases and mammals have five [1]. In 1999, however, an entirely new category of polymerases was discovered in prokaryotes and eukaryotes [2-4] -the lesion-bypass DNA polymerases. The function of lesion-bypass polymerases is to replicate past lesion-containing DNA templates in a process called translesion synthesis [5][6][7]. Now at least 16 DNA polymerases are known in eukaryotes [8] and five in bacteria [9]. Furthermore, since 1999, crystal structures of DNA polymerases, including those containing lesions, have provided new structural insights into the mechanistic aspects of translesion synthesis and polymerase stalling associated with DNA lesions. For a review of the structures and mechanisms of DNA polymerases up to the year 2005, see Ref.[10].Here, we discuss the structural and functional features of representative high-fidelity and lesion-bypass DNA polymerases (Box 1) and how these features affect the processing of certain forms of DNA damage. The lesions considered are derived from reactions of intermediates produced by endogenous sources or from the metabolic activation of environmental genotoxic

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“…Aquatic organisms are frequently exposed to numerous environmental pollutants including polycyclic aromatic hydrocarbons (PAHs) and heavy metals (Rainbow, 1995;Xue and Warshawsky, 2005;Wan et al, 2009). Heavy metals such as copper (Cu) and cadmium (Cd) can induce excessive production of reactive oxygen species (ROS) in cells, which cause oxidative modification of the major cellular macromolecules (Cecconi et al, 2002).…”

Section: Introductionmentioning

confidence: 99%