Role of Metabolic Activation and the TRPA1 Receptor in the Sensory Irritation Response to Styrene and Naphthalene

Lanosa, Michael J.; Willis, Daniel N.; Jordt, Sven E.; Morris, John B.

doi:10.1093/toxsci/kfq057

Cited by 37 publications

(23 citation statements)

References 36 publications

(58 reference statements)

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“…TRPA1 is also activated by many non-electrophilic chemicals, including natural products such as menthol, carvacrol and sesquiterpene irritants (Escalera et al, 2008) Finally, some chemicals that do not activate TRPA1 in vitro are metabolically converted into TRPA1 agonists in vivo , eliciting TRPA1-dependent sensory irritation and other toxicological effects. Examples include styrene and naphthalene that require Cytochrome P450 activity to cause TRPA1-dependent respiratory irritation in mice in vivo (Lanosa et al, 2010), and chemotherapy drugs such as cyclophosphamide and ifosfamide. The latter are metabolized forming acrolein as a by-product that, if not scavenged, damages the bladder to cause hemorrhagic cystitis and TRPA1-dependent visceral pain (Conklin et al, 2009; Pereira et al, 2013).…”

Section: Implications For Toxicological Testingmentioning

confidence: 99%

TRPA1: Acrolein meets its target

Achanta

Jordt

2017

Toxicology and Applied Pharmacology

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Section: Implications For Toxicological Testingmentioning

confidence: 99%

TRPA1: Acrolein meets its target

Achanta

Jordt

2017

Toxicology and Applied Pharmacology

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“…In one of the styrene toxicity studies, Alarie [43] and his coworkers suggested that the sensory irritation of the upper airways by styrene could result from the adduction of styrene metabolites with sulfhydryl groups on the free afferent trigeminal nerve endings located at the surface of the nasal mucosa. Recently, Lanosa and co-workers found a close correlation between metabolic activation of styrene and the sensory irritation response to styrene [44]. Thus, the understanding of the relationship between protein covalent binding and styrene toxicity and further identification of the reactive metabolite-modified proteins are crucial steps to elucidate the mechanisms of styrene-induced cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Evidence for cellular protein covalent binding derived from styrene metabolite

Wei

Jin

Chung

et al. 2010

Chemico-Biological Interactions

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Styrene is one of the most important industrial intermediates consumed in the world. Human exposure to styrene occurs mainly in the reinforced plastics industry, particularly in developing countries. Styrene has been found to be hepatotoxic and pneumotoxic in humans and animals. The biochemical mechanisms of styrene-induced toxicities remain unknown. Albumin and hemoglobin adduction derived from styrene oxide, a major reactive metabolite of styrene, has been reported in blood samples obtained from styrene exposed workers. The objectives of the current study focused on cellular protein covalent binding of styrene metabolite and its correlation with cytotoxicity induced by styrene. We found that radioactivity was bound to cellular proteins obtained from mouse airway trees after incubation with 14C-styrene. Microsomal incubation studies showed that the observed protein covalent binding required the metabolic activation of styrene. The observed radioactivity binding in protein samples obtained from the cultured airways and microsomal incubations were significantly suppressed by co-incubation with disulfiram, a CYP2E1 inhibitor, although disulfiram apparently did not show a protective effect against the cytotoxicity of styrene. A 2-fold increase in radioactivity bound to cellular proteins was detected in cells stably transfected with CYP2E1 compared to the wild-type cells after 14C-styrene exposure. With the polyclonal antibody developed in our lab, we detected cellular protein adduction derived from styrene oxide at cysteinyl residues in cells treated with styrene. Competitive immunoblot studies confirmed the modification of cysteine residues by styrene oxide. Cell culture studies showed that the styrene-induced protein modification and cell death increased with the increasing concentration of styrene exposure. In conclusion, we detected cellular protein covalent modification by styrene oxide in microsomal incubations, cultured cells, and mouse airways after exposure to styrene and found a good correlation between styrene-induced cytotoxicity and styrene oxide-derived cellular protein adduction.

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“…These include uric acid, glutathione, ascorbic acid, carotenes, lipoic acid, tocopherol, ubiquinol, ammonia, carbonic acid, phosphate, and enzymes. In certain incidences these enzymes produce more toxic metabolites (5)(6)(7). In severe exposures these protective chemicals are saturated and the reactive chemicals react with lung tissues, damaging lung and its delicate alveolar sacs (8).…”

mentioning

confidence: 99%

Sensory Detection and Responses to Toxic Gases: Mechanisms, Health Effects, and Countermeasures

Bessac

Jordt²

2010

Proceedings of the American Thoracic Society

118

112

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The inhalation of reactive gases and vapors can lead to severe damage of the airways and lung, compromising the function of the respiratory system. Exposures to oxidizing, electrophilic, acidic, or basic gases frequently occur in occupational and ambient environments. Corrosive gases and vapors such as chlorine, phosgene, and chloropicrin were used as warfare agents and in terrorist acts. Chemical airway exposures are detected by the olfactory, gustatory, and nociceptive sensory systems that initiate protective physiological and behavioral responses. This review focuses on the role of airway nociceptive sensory neurons in chemical sensing and discusses the recent discovery of neuronal receptors for reactive chemicals. Using physiological, imaging, and genetic approaches, Transient Receptor Potential (TRP) ion channels in sensory neurons were shown to respond to a wide range of noxious chemical stimuli, initiating pain, respiratory depression, cough, glandular secretions, and other protective responses. TRPA1, a TRP ion channel expressed in chemosensory C-fibers, is activated by almost all oxidizing and electrophilic chemicals, including chlorine, acrolein, tear gas agents, and methyl isocyanate, the highly noxious chemical released in the Bhopal disaster. Chemicals likely activate TRPA1 through covalent protein modification. Animal studies using TRPA1 antagonists or TRPA1-deficient mice confirmed the role of TRPA1 in chemically induced respiratory reflexes, pain, and inflammation in vivo. New research shows that sensory neurons are not merely passive sensors of chemical exposures. Sensory channels such as TRPA1 are essential for maintenance of airway inflammation in asthma and may contribute to the progression of airway injury following high-level chemical exposures.

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Role of Metabolic Activation and the TRPA1 Receptor in the Sensory Irritation Response to Styrene and Naphthalene

Cited by 37 publications

References 36 publications

TRPA1: Acrolein meets its target

TRPA1: Acrolein meets its target

Evidence for cellular protein covalent binding derived from styrene metabolite

Sensory Detection and Responses to Toxic Gases: Mechanisms, Health Effects, and Countermeasures

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