Microsomal metabolism of dibenz[a,c]anthracene, dibenz[a,h]anthracene and dibenz[a,j]anthracene to bis-dihydrodiols and polyhydroxylated products

Lecoq, Sophie; Chalvet, O.; Strapelias, H.; Grover, Philip L.; Phillips, David H.; Duquesne, M.

doi:10.1016/0009-2797(91)90087-n

Cited by 25 publications

(23 citation statements)

References 27 publications

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“…Similarly, there is a substantive body of evidence that confirms the hypothesis implicating the formation of bay region diol epoxides as the major mechanism of action for both the genotoxicity and carcinogenicity induced by these PAHs (Cheung et al, 1993;Fuchs et al, 1993aFuchs et al, , 1993bGlatt et al, 1993;Lecoq et al, 1989Lecoq et al, , 1991aWood, 1979). It is also of note that these three compounds, as well as benzo[a]pyrene, induced neoplastic cell transformation in at least one cell line (ATSDR, 1995).…”

Section: Developmental Effectsmentioning

confidence: 73%

Atsdr Evaluation of Health Effects of Chemicals. Iv. Polycyclic Aromatic Hydrocarbons (PAHs): Understanding a Complex Problem

et al. 1996

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Polycyclic Aromatic Hydrocarbons (PAHs) are a group of chemicals that are formed during the incomplete burning of coal, oil, gas, wood, garbage, or other organic substances, such as tobacco and charbroiled meat. There are more than 100 PAHs. PAHs generally occur as complex mixtures (for example, as part of products such as soot), not as single compounds. PAHs are found throughout the environment in the air, water, and soil. As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals, including PAHs (ATSDR, 1995), found at facilities on the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). These profiles include information on health effects of chemicals from different routes and durations of exposure, their potential for exposure, regulations and advisories, and the adequacy of the existing database. Assessing the health effects of PAHs is a major challenge because environmental exposures to these chemicals are usually to complex mixtures of PAHs with other chemicals. The biological consequences of human exposure to mixtures of PAHs depend on the toxicity, carcinogenic and noncarcinogenic, of the individual components of the mixture, the types of interactions among them, and confounding factors that are not thoroughly understood. Also identified are components of exposure and health effects research needed on PAHs that will allow estimation of realistic human health risks posed by exposures to PAHs. The exposure assessment component of research should focus on (1) development of reliable analytical methods for the determination of bioavailable PAHs following ingestion, (2) estimation of bioavailable PAHs from environmental media, particularly the determination of particle-bound PAHs, (3) data on ambient levels of PAHs metabolites in tissues/fluids of control populations, and (4) the need for a critical evaluation of current levels of PAHs found in environmental media including data from hazardous waste sites. The health effects component should focus on obtaining information on (1) the health effects of mixtures of PAHs particularly their noncarcinogenic effects in humans, and (2) their toxicokinetics. This report provides excerpts from the toxicological profile of PAHs (ATSDR, 1995) that contains more detailed information.

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Section: Developmental Effectsmentioning

confidence: 73%

Atsdr Evaluation of Health Effects of Chemicals. Iv. Polycyclic Aromatic Hydrocarbons (PAHs): Understanding a Complex Problem

et al. 1996

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“…However, specific methylated phenanthrenes, which direct the metabolic fate there is a substantive body of evidence that confirms the hypothesis implicating the formation of bay region diol epoxides as the major mechanism of action for both the genotoxicity and carcinogenicity induced by these PAHs (Cheung et al 1993;Fuchs et al 1993aFuchs et al , 1993bGlatt et al 1993;Lecoq et al 1989Lecoq et al , 1991aWood 1979). It is also of note that these three compounds, as well as benzo[a]pyrene, induced neoplastic cell transformation in at least one cell line (see Table 2-5).…”

Section: Health Effectsmentioning

confidence: 82%

The Gulf Oil Spill

2011

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“…It is bioactivated to the proximate carcinogen 3,4-dihydrodiol and subsequently to the ultimate carcinogen 3,4-diol-1,2-epoxides (Fig. (150)), which can covalently bind to cellular macromolecules [1186,1187]. The 1,2-and 5,6-dihydrodiols had no tumor-initiating activity.…”

Section: Db[ah]mentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

145

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Microsomal metabolism of dibenz[a,c]anthracene, dibenz[a,h]anthracene and dibenz[a,j]anthracene to bis-dihydrodiols and polyhydroxylated products

Cited by 25 publications

References 27 publications

Atsdr Evaluation of Health Effects of Chemicals. Iv. Polycyclic Aromatic Hydrocarbons (PAHs): Understanding a Complex Problem

Atsdr Evaluation of Health Effects of Chemicals. Iv. Polycyclic Aromatic Hydrocarbons (PAHs): Understanding a Complex Problem

The Gulf Oil Spill

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

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