The metabolism of nonane, a JP-8 jet fuel component, by human liver microsomes, P450 isoforms and alcohol dehydrogenase and inhibition of human P450 isoforms by JP-8

Edwards, Jeffrey E.; Rose, Randy L.; Hodgson, Ernest

doi:10.1016/j.cbi.2004.12.003

Cited by 22 publications

(17 citation statements)

References 26 publications

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“…This involves the development of an analytical method for the substrate and its metabolites, measurement of metabolic activity with human cell preparations such as liver microsomes and/or cytosol followed by identification of the enzymes involved, as [45] well as their isoforms and polymorphic variants. The study of variation between individuals is of critical importance.…”

Section: Introductionmentioning

confidence: 99%

Human metabolic interactions of environmental chemicals

Hodgson

Rose

2007

J Biochem & Molecular Tox

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Investigations utilizing recombinant human xenobiotic-metabolizing enzymes as well as human hepatocytes have revealed a number of interactions not only between different environmental chemicals (ECs) but also between ECs and endogenous metabolites. Organophosphorus insecticides (OPs) are potent inhibitors of the human metabolism of carbaryl, carbofuran, DEET and fipronil, as well as the jet fuel components, nonane and naphthalene. OPs are potent irreversible inhibitors of testosterone metabolism by cytochrome P450 (CYP) 3A4 and of estradiol metabolism by CYP3A4 and CYP1A2. All of these CYP inhibitions are believed to be due to the release of reactive sulfur during CYP-catalyzed oxidative desulfuration. It has also been shown that the esterase(s) responsible for the initial step in permethrin metabolism in human liver is inhibited by both chlorpyrifos oxon and carbaryl. A number of pesticides, including chlorpyrifos, fipronil and permethrin, and the repellent, DEET, have been shown to be inducers of CYP isoforms in human hepatocytes, with fipronil being the most potent. Several agrochemicals, including fipronil and the pyrethroids, permethrin and deltamethrin, show toxicity toward human hepatocytes with fipronil being the most potent in this regard. Endosulfan-alpha, which has shown promise as a model substrate for phenotyping CYP3A4 and CYP2B6 in human liver microsomes, is also an inducer of CYP2B6, acting through the PXR receptor.

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Section: Introductionmentioning

confidence: 99%

Human metabolic interactions of environmental chemicals

Hodgson

Rose

2007

J Biochem & Molecular Tox

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“…Aromatic fuel hydrocarbons share a common major metabolic pathway, as indicated in work with CYP450 2E1 (Haddad et al, 1999). Alkanes have been shown to be primarily metabolized by CYP1A2 and 2B6 (Anand et al, 2007;Edwards et al, 2005). The result of competitive inhibition of metabolism between fuel hydrocarbons is the presence of higher concentrations of the marker constituents in blood and tissue, over a longer duration than would occur following individual chemical exposure.…”

Section: Discussionmentioning

confidence: 96%

“…The metabolism of n-alkanes and some iso-alkanes occurs primarily by P450 CYP 1A2 and CYP 2B6 (Edwards et al, 2005). Competitive inhibition of metabolism was described for hydrocarbon marker sub-models and Lumps 1 and 2, within the light fuel fraction and the intermediate fraction of fuel.…”

Section: Metabolic Interactions For the Light Intermediate And Heavymentioning

confidence: 99%

Development of a physiologically based pharmacokinetic model for inhalation of jet fuels in the rat

Martin

Campbell

Tremblay

et al. 2011

Inhalation Toxicology

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The pharmacokinetic behavior of the majority of jet fuel constituents has not been previously described in the framework of a physiologically based pharmacokinetic (PBPK) model for inhalation exposure. Toxic effects have been reported in multiple organ systems, though exposure methods varied across studies, utilizing either vaporized or aerosolized fuels. The purpose of this work was to assess the pharmacokinetics of aerosolized and vaporized fuels, and develop a PBPK model capable of describing both types of exposures. To support model development, n-tetradecane and n-octane exposures were conducted at 89 mg/m(3) aerosol+vapor and 1000-5000 ppm vapor, respectively. Exposures to JP-8 and S-8 were conducted at ~900-1000 mg/m(3), and ~200 mg/m(3) to a 50:50 blend of both fuels. Sub-models were developed to assess the behavior of representative constituents and grouped unquantified constituents, termed "lumps", accounting for the remaining fuel mass. The sub-models were combined into the first PBPK model for petroleum and synthetic jet fuels. Inhalation of hydrocarbon vapors was described with simple gas-exchange assumptions for uptake and exhalation. For aerosol droplets systemic uptake occurred in the thoracic region. Visceral tissues were described using perfusion and diffusion-limited equations. The model described kinetics at multiple fuel concentrations, utilizing a chemical "lumping" strategy to estimate parameters for fractions of speciated and unspeciated hydrocarbons and gauge metabolic interactions. The model more accurately simulated aromatic and lower molecular weight (MW) n-alkanes than some higher MW chemicals. Metabolic interactions were more pronounced at high (~2700-1000 mg/m(3)) concentrations. This research represents the most detailed assessment of fuel pharmacokinetics to date.

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“…Chlorpyrifos (CPS), fipronil, and nonane can all be metabolized by HLM and specific CYP isoforms [1,2,9]. In this study, metabolic interactions between CPS and fipronil, and CPS and nonane, were investigated.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, nonane, a component of jet-propulsion fuel 8 (JP-8) and other fossil fuels, is metabolized to 2-nonanol and 2-nonanone by HLM, and that CYP2B6 and 2E1 are primarily responsible for this activity. In addition, CYP1A2 is also responsible for 2-nonanol production [2].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of fipronil and nonane metabolism in human liver microsomes and human cytochrome P450 isoforms by chlorpyrifos

Joo

Choi

Rose

et al. 2007

J Biochem & Molecular Tox

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Previous studies have established that chlorpyrifos (CPS), fipronil, and nonane can all be metabolized by human liver microsomes (HLM) and a number of cytochrome P450 (CYP) isoforms. However, metabolic interactions between these three substrates have not been described. In this study the effect of either coincubation or preincubation of CPS with HLM or CYP isoforms with either fipronil or nonane as substrate was investigated. In both co- and preincubation experiments, CPS significantly inhibited the metabolism of fipronil or nonane by HLM although CPS inhibited the metabolism of fipronil more effectively than that of nonane. CPS significantly inhibited the metabolism of fipronil by CYP3A4 as well as the metabolism of nonane by CYP2B6. In both cases, preincubation with CPS caused greater inhibition than coincubation, suggesting that the inhibition is mechanism based.

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The metabolism of nonane, a JP-8 jet fuel component, by human liver microsomes, P450 isoforms and alcohol dehydrogenase and inhibition of human P450 isoforms by JP-8

Cited by 22 publications

References 26 publications

Human metabolic interactions of environmental chemicals

Human metabolic interactions of environmental chemicals

Development of a physiologically based pharmacokinetic model for inhalation of jet fuels in the rat

Inhibition of fipronil and nonane metabolism in human liver microsomes and human cytochrome P450 isoforms by chlorpyrifos

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