Limonene hydroperoxide analogues differ in allergenic activity

Christensson, Johanna Bråred; Johansson, Staffan; Hagvall, Lina; Jonsson, Charlotte; Börje, Anna; Karlberg, Ann‐Therése

doi:10.1111/j.1600-0536.2008.01442.x

Cited by 73 publications

(81 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A large fraction of this literature focuses on the allergenic properties of limonene, which were shown to be due to limonene hydroperoxide (25,(36)(37)(38). This direct parallel to bacterial toxicity suggests a general cellular damage mechanism for limonene hydroperoxide.…”

Section: Discussionmentioning

confidence: 99%

Acute Limonene Toxicity in Escherichia coli Is Caused by Limonene Hydroperoxide and Alleviated by a Point Mutation in Alkyl Hydroperoxidase AhpC

Chubukov

Mingardon

Schackwitz

et al. 2015

Appl Environ Microbiol

View full text Add to dashboard Cite

f Limonene, a major component of citrus peel oil, has a number of applications related to microbiology. The antimicrobial properties of limonene make it a popular disinfectant and food preservative, while its potential as a biofuel component has made it the target of renewable production efforts through microbial metabolic engineering. For both applications, an understanding of microbial sensitivity or tolerance to limonene is crucial, but the mechanism of limonene toxicity remains enigmatic. In this study, we characterized a limonene-tolerant strain of Escherichia coli and found a mutation in ahpC, encoding alkyl hydroperoxidase, which alleviated limonene toxicity. We show that the acute toxicity previously attributed to limonene is largely due to the common oxidation product limonene hydroperoxide, which forms spontaneously in aerobic environments. The mutant AhpC protein with an L-to-Q change at position 177 (AhpC L177Q ) was able to alleviate this toxicity by reducing the hydroperoxide to a more benign compound. We show that the degree of limonene toxicity is a function of its oxidation level and that nonoxidized limonene has relatively little toxicity to wild-type E. coli cells. Our results have implications for both the renewable production of limonene and the applications of limonene as an antimicrobial. L imonene, the major component of citrus peel oil, has a variety of industrial and microbiological applications. Its antimicrobial properties make it a popular component of disinfectants and food preservatives and an environmentally friendly solvent used at the industrial scale (1-4). More recently, limonene or its hydrogenated forms have been identified to be potential jet fuel components (5-7). As such, the anticipation of a greater global demand for limonene has provided significant motivation for the renewable production of this compound from plant biomass through a microbial process (8-10), and recent efforts to optimize production have resulted in titers of over 400 mg/liter at the bench scale (11). In this context, the toxicity of limonene to the microbial host presents a major challenge, as the accumulation of toxic products limits growth and metabolic activity.Curiously, the toxicity of limonene has been reported to be significantly higher than that of other monoterpenes or solvents with similar hydrophobicities (12, 13), suggesting that this acute toxicity is due to something other than its solvent-like properties. However, molecular-level studies of limonene toxicity in microbes are limited. While several studies in Escherichia coli have noted an impact of limonene on lipid composition (14) and suggested a role for reactive oxygen species (ROS) (15), no specific hypothesis for how limonene causes these cellular perturbations has been proposed.In this work, we investigated the basis of limonene toxicity in the model Gram-negative bacterium E. coli. We identified a mutant with significantly enhanced tolerance to limonene and show that the majority of the toxicity in wild-type (WT) cells is due no...

show abstract

Section: Discussionmentioning

confidence: 99%

Acute Limonene Toxicity in Escherichia coli Is Caused by Limonene Hydroperoxide and Alleviated by a Point Mutation in Alkyl Hydroperoxidase AhpC

Chubukov

Mingardon

Schackwitz

et al. 2015

Appl Environ Microbiol

View full text Add to dashboard Cite

show abstract

“…Depending on the stability of the oxidation products that are formed, a difference in the sensitizing potency of the oxidized compounds can be seen. Some of the most commonly used fragrances (Table ) have been shown to easily autoxidize and form oxidation products identified as potent sensitizers in predictive animal tests …”

Section: Prehaptensmentioning

confidence: 99%

Activation of non‐sensitizing or low‐sensitizing fragrance substances into potent sensitizers – prehaptens and prohaptens

et al. 2013

Self Cite

View full text Add to dashboard Cite

SummaryExperimental and clinical studies have shown that fragrance substances can act as prehaptens or prohaptens. They form allergens that are more potent than the parent substance by activation outside or in the skin via abiotic (chemical and physical factors) and/or biotic activation, thus, increasing the risk of sensitization. In the present review a series of fragrance substances with well documented abiotic and/or biotic activation are given as indicative and illustrative examples of the general problem. Commonly used fragrance substances, also found in essential oils, autoxidize on contact with air, forming potent sensitizers that can be an important source for contact allergy to fragrances and fragranced products. Some of them can act as prohaptens and be activated in the skin as well. The experimental findings are confirmed in large clinical studies. When substances with structural alerts for acting as prohaptens and/or prehaptens are identified, the possibility of generating new potent allergens should be considered. Predictive testing should include activation steps. Further experimental and clinical research regarding activation of fragrance substances is needed to increase consumer safety.Key words: abiotic and biotic activation; autoxidation; directive 76/768/ECC; fragrance allergens; prehaptens; prohaptens; SCCS; scientific opinion.Many fragrance substances act as haptens, that is, low molecular weight chemicals that are immunogenic when attached to a carrier protein in the skin. This means that the substances can directly react with skin proteins, owing to inherent chemical properties. Experimental and clinical studies have shown that there are also fragrance substances that act as prehaptens or prohaptens, forming Accepted for publication 29 June 2013 allergens that are more potent than the parent substance by activation outside or in the skin via abiotic (chemical and physical factors) and/or biotic activation, and thus increasing the risk of sensitization.A prehapten is a chemical that is itself non-sensitizing or low-sensitizing, but that is transformed into a hapten outside the skin by chemical transformation (air

show abstract

“…This modified method was used in our previous work with epoxy resin analogs as well as in other studies by the group. 38,44 For ethical reasons, we did not want to repeatedly perform LLNA experiments and therefore only ERM 5 was compared with DGEBA.…”

Section: Skin Sensitizing Potency Studiesmentioning

confidence: 99%

Epoxy Resin Monomers with Reduced Skin Sensitizing Potency

O’Boyle

Niklasson

Tehrani‐Bagha

et al. 2014

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

Epoxy resin monomers, including diglycidyl ethers of bisphenol A and F (DGEBA and DGEBF), are extensively used as building blocks for thermosetting polymers. However, they are known to cause widespread contact allergy. This research describes a number of alternative epoxy resin monomers, designed with the aim of reducing the skin sensitizing potency whilst maintaining the ability to form thermosetting polymers. The compounds were designed, synthesized, assessed for skin sensitizing potency using the in vivo murine local lymph node assay, and tested for technical applicability using thermogravimetric analysis and differential scanning calorimetry. All the novel epoxy resin monomers had decreased skin sensitization potencies compared to DGEBA and DGEBF. With respect to EC3 values, which is the estimated concentration of a substance required to induce a 3-fold increase in sensitization compared to a control, the best of the new monomers had a value approximately 2.5 times higher than those of DGEBA and DGEBF. The diepoxides were reacted with triethylenetetramine and four out of the six novel monomers gave polymers with a thermal stability comparable to that obtained with DGEBA and DGEBF. The new epoxy resin monomers have the potential to replace DGEBA and DGEBF, leading to a decreased incidence of contact allergy due to epoxy resins, decreased healthcare costs, and an increased quality of life for those handling thermosetting materials.

show abstract

Limonene hydroperoxide analogues differ in allergenic activity

Cited by 73 publications

References 30 publications

Acute Limonene Toxicity in Escherichia coli Is Caused by Limonene Hydroperoxide and Alleviated by a Point Mutation in Alkyl Hydroperoxidase AhpC

Acute Limonene Toxicity in Escherichia coli Is Caused by Limonene Hydroperoxide and Alleviated by a Point Mutation in Alkyl Hydroperoxidase AhpC

Activation of non‐sensitizing or low‐sensitizing fragrance substances into potent sensitizers – prehaptens and prohaptens

Epoxy Resin Monomers with Reduced Skin Sensitizing Potency

Contact Info

Product

Resources

About