Xenobiotic metabolizing enzyme activities in cells used for testing skin sensitization in vitro

Fabian, Eric; Vogel, Denise; Blatz, Veronika; Ramı́rez, Tzutzuy; Kolle, Susanne N.; Eltze, Tobias; Ravenzwaay, Bennard van; Oesch, Franz; Landsiedel, Robert

doi:10.1007/s00204-013-1090-9

Cited by 23 publications

(25 citation statements)

References 63 publications

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“…Diethylenetriamine and resorcinol are putative pro-haptens. They are not detectable in the cell-free DPRA and may not be activated in the cellular assays due to a limited metabolic capacity (Fabian et al, 2013;Oesch et al, 2014). Benzoyl peroxide was strongly positive in the DPRA but negative in the KeratinoSens™ and h-CLAT.…”

Section: False Negative and False Positivesmentioning

confidence: 98%

See 1 more Smart Citation

Assessing skin sensitization hazard in mice and men using non-animal test methods

Urbisch

Mehling²,

Guth

et al. 2015

Regulatory Toxicology and Pharmacology

313

253

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Sensitization, the prerequisite event in the development of allergic contact dermatitis, is a key parameter in both hazard and risk assessments. The pathways involved have recently been formally described in the OECD adverse outcome pathway (AOP) for skin sensitization. One single non-animal test method will not be sufficient to fully address this AOP and in many cases the use of a battery of tests will be necessary. A number of methods are now fully developed and validated. In order to facilitate acceptance of these methods by both the regulatory and scientific communities, results of the single test methods (DPRA, KeratinoSens, LuSens, h-CLAT, (m)MUSST) as well for a the simple '2 out of 3' ITS for 213 substances have been compiled and qualitatively compared to both animal and human data. The dataset was also used to define different mechanistic domains by probable protein-binding mechanisms. In general, the non-animal test methods exhibited good predictivities when compared to local lymph node assay (LLNA) data and even better predictivities when compared to human data. The '2 out of 3' prediction model achieved accuracies of 90% or 79% when compared to human or LLNA data, respectively and thereby even slightly exceeded that of the LLNA.

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Section: False Negative and False Positivesmentioning

confidence: 98%

“…This can be explained by the fact, that some members of this group might require enzymatic activation, which is absent in the in chemico assay. The cell-based test methods also have only limited metabolic capacities (Oesch et al, 2014;Fabian et al, 2013) and thus have limitations in detecting putative pro-haptens.…”

Section: Mechanistic Domainsmentioning

confidence: 99%

Assessing skin sensitization hazard in mice and men using non-animal test methods

Urbisch

Mehling²,

Guth

et al. 2015

Regulatory Toxicology and Pharmacology

313

253

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“…In most of these cases, sensitizers lacking electrophilic moieties were transformed to quinones, quinone imines or quinone methides as reactive intermediates, suggesting autoxidation. 31 The m/z values indicate that the reactive intermediates formed covalent bonds with the peptide following Michael additions (i.e., for 3, 4, 5, 6,9,10,11,12,13,16,17). As an example, the oxidative activation of the pre-hapten hydroquinone (6) to the highly electrophilic Michael acceptor para-benzoquinone and the molecular structure of its corresponding adduct is shown in Figure 3.…”

Section: A4mentioning

confidence: 99%

Assessment of Pre- and Pro-haptens Using Nonanimal Test Methods for Skin Sensitization

Urbisch

Becker

Honarvar

et al. 2016

Chem. Res. Toxicol.

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Because of ethical and regulatory reasons, several nonanimal test methods to assess the skin sensitization potential of chemicals have been developed and validated. In contrast to in vivo methods, they lack or provide limited metabolic capacity. For this reason, identification of pro-haptens but also pre-haptens, which require molecular transformations to gain peptide reactivity, is a challenge for these methods. In this study, 27 pre- and pro-haptens were tested using nonanimal test methods. Of these, 18 provided true positive results in the direct peptide reactivity assay (DPRA; sensitivity of 67%), although lacking structural alerts for direct peptide reactivity. The reaction mechanisms leading to peptide depletion in the DPRA were therefore elucidated using mass spectrometry. Hapten-peptide adducts were identified for 13 of the 18 chemicals indicating that these pre-haptens were activated and that peptide binding occurred. Positive results for five of the 18 chemicals can be explained by dipeptide formations or the oxidation of the sulfhydryl group of the peptide. Nine of the 27 chemicals were tested negative in the DPRA. Of these, four yielded true positive results in the keratinocyte and dendritic cell based assays. Likewise, 16 of the 18 chemicals tested positive in the DPRA were also positive in either one or both of the cell-based assays. A combination of DPRA, KeratinoSens, and h-CLAT used in a 2 out of 3 weight of evidence (WoE) approach identified 22 of the 27 pre- and pro-haptens correctly (sensitivity of 81%), exhibiting a similar sensitivity as for directly acting haptens. This analysis shows that the combination of in chemico and in vitro test methods is suitable to identify pre-haptens and the majority of pro-haptens.

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“…Dressler and Appelqvist (2006) tentatively identified NAT1 to mediate in the rat skin the acetylation of para-aminophenol. NAT1 activity is not stable leading to quite variable results (Fabian et al 2013). …”

Section: Xenobiotica-metabolizing Enzymes In the Rat Skinmentioning

confidence: 99%

“…Fabian et al (2013) reported that in U937 und THP-1 (dendritic cell lines from the German Collection of Microorganisms and Cell Cultures) and in the keratinocytic cell lines LuSens (developed by BASF SE) and KeratinoSens ® (developed by Givaudan) EROD, PROD and BROD activities were below the LOD.…”

Section: Xenobiotica-metabolizing Enzymes In the Human Skin Includingmentioning

confidence: 99%

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

2018

Self Cite

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Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. This review collects available information of which—taken with great caution because of the still very limited data—the most salient points are: in the skin of all animal species and skin-derived in vitro systems considered in this review cytochrome P450 (CYP)-dependent monooxygenase activities (largely responsible for initiating xenobiotica metabolism in the organ which provides most of the xenobiotica metabolism of the mammalian organism, the liver) are very low to undetectable. Quite likely other oxidative enzymes [e.g. flavin monooxygenase, COX (cooxidation by prostaglandin synthase)] will turn out to be much more important for the oxidative xenobiotic metabolism in the skin. Moreover, conjugating enzyme activities such as glutathione transferases and glucuronosyltransferases are much higher than the oxidative CYP activities. Since these conjugating enzymes are predominantly detoxifying, the skin appears to be predominantly protected against CYP-generated reactive metabolites. The following recommendations for the use of experimental animal species or human skin in vitro models may tentatively be derived from the information available to date: for dermal absorption and for skin irritation esterase activity is of special importance which in pig skin, some human cell lines and reconstructed skin models appears reasonably close to native human skin. With respect to genotoxicity and sensitization reactive-metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the Conclusions section in the end of this review.

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Xenobiotic metabolizing enzyme activities in cells used for testing skin sensitization in vitro

Cited by 23 publications

References 63 publications

Assessing skin sensitization hazard in mice and men using non-animal test methods

Assessing skin sensitization hazard in mice and men using non-animal test methods

Assessment of Pre- and Pro-haptens Using Nonanimal Test Methods for Skin Sensitization

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models

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