Binding of apolar molecules by serum albumin

Vandenbelt, J. M.; Hansch, Corwin; Church, Clinton D.

doi:10.1021/jm00278a001

Cited by 44 publications

(16 citation statements)

References 8 publications

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“…As 4-chloroaniline and its reactive metabolites are known to bind covalently to hemoglobin and to proteins of liver and kidney (IPCS, 2003) and to bovine serum albumin (Vandenbelt, Hansch, & Church, 1972), the lack of metabolism of this chemical in skin explants could be due to extensive covalent binding to the extracellular matrix, reducing the free fraction available for metabolism. One metabolite was identified in S9 incubations as 4-chloro-N-acetanilide, which is known to be produced in vivo, together with a hydroxide (4-aminophenol; IPCS, 2003).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the metabolism of 10 cosmetics‐relevant chemicals in EpiSkin™ S9 subcellular fractions and in vitro human skin explants

Géniès

Jacques

Duplan

et al. 2019

J of Applied Toxicology

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An understanding of the bioavailability of topically applied cosmetics ingredients is key to predicting their local skin and systemic toxicity and making a safety assessment. We investigated whether short-term incubations with S9 from the reconstructed epidermal skin model, EpiSkin™, would give an indication of the rate of chemical metabolism and produce similar metabolites to those formed in incubations with human skin explants. Both have advantages: EpiSkin™ S9 is a higher-throughput assay, while the human skin explant model represents a longer incubation duration (24 hours) model integrating cutaneous distribution with metabolite formation. Here, we compared the metabolism of 10 chemicals (caffeine, vanillin, cinnamyl alcohol, propylparaben, 4-amino-3-nitrophenol, resorcinol, 4-chloroaniline, 2-amino-3-methyl-3H-imidazo[4,5-F]quinoline and 2-acetyl aminofluorene) in both models. Both models were shown to have functional Phase 1 and 2 enzymes, including cytochrome P450 activities. There was a good concordance between the models with respect to the level of metabolism (stable vs. slowly vs. extensively metabolized chemicals) and major early metabolites produced for eight chemicals. Discordant results for two chemicals were attributed to a lack of the appropriate cofactor (NADP + ) in S9 incubations (cinnamyl alcohol) and protein binding influencing chemical uptake in skin explants (4-chloroaniline). These data support the use of EpiSkin™ S9 as a screening assay to provide an initial indication of the metabolic stability of a chemical applied topically. If required, chemicals that are not metabolized by Epi-Skin™ S9 can be tested in longer-term incubations with in vitro human explant skin to determine whether it is slowly metabolized or not metabolized at all.

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Section: Discussionmentioning

confidence: 99%

Comparison of the metabolism of 10 cosmetics‐relevant chemicals in EpiSkin™ S9 subcellular fractions and in vitro human skin explants

Géniès

Jacques

Duplan

et al. 2019

J of Applied Toxicology

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“…One hypothesis as to why this metabolite was not detected in in vitro skin could be that 4‐chloroaniline was bound to the extracellular skin proteins in the epidermis, rather than entering the cells, and was therefore not available for metabolism by XMEs. This is supported by the fact that 4‐chloroaniline and its reactive metabolites bind to proteins,e.g., hemoglobin, liver and kidney proteins (IPCS, ) and BSA (Vandenbelt, Hansch, & Church, ). Likewise, in our skin explant assay, ~20% of the radioactivity detected in the culture medium was bound to proteins (most likely to BSA).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the metabolism of 10 chemicals in human and pig skin explants

Géniès

Jamin

Debrauwer

et al. 2018

J of Applied Toxicology

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Skin metabolism is important to consider when assessing local toxicity and/or penetration of chemicals and their metabolites. If human skin supply is limited, pig skin can be used as an alternative. To identify any species differences, we have investigated the metabolism of 10 chemicals in a pig and human skin explant model. Phase I metabolic pathways in skin from both species included those known to occur via cytochrome P450s, esterases, alcohol dehydrogenases and aldehyde dehydrogenases. Common Phase II pathways were glucuronidation and sulfation but other conjugation pathways were also identified. Chemicals not metabolized by pig skin (caffeine, IQ and 4‐chloroaniline) were also not metabolized by human skin. Six chemicals metabolized by pig skin were metabolized to a similar extent (percentage parent remaining) by human skin. Human skin metabolites were also detected in pig skin incubations, except for one unidentified minor vanillin metabolite. Three cinnamyl alcohol metabolites were unique to pig skin but represented minor metabolites. There were notable species differences in the relative amounts of common metabolites. The difference in the abundance of the sulfate conjugates of resorcinol and 4‐amino‐3‐nitrophenol was in accordance with the known lack of aryl sulfotransferase activity in pigs. In conclusion, while qualitative comparisons of metabolic profiles were consistent between pig and human skin, there were some quantitative differences in the percentage of metabolites formed. This preliminary assessment suggests that pig skin is metabolically competent and could be a useful tool for evaluating potential first‐pass metabolism before testing in human‐derived tissues.

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“…Hydrophobic chemicals have been found to sorb to organic components in aqueous media, thereby reducing their bioavailability. This reduction in bioavailability due sorption has been well explored in pharmaceutical applications (Paci"ci and Viani, 1992) and to a lesser extent in ecotoxicology (Hansch et al, 1965;Kiehs et al, 1966;Vandenbelt, 1972;Fisher et al, 1993;Vaes et al, 1996).…”

Section: Discussionmentioning

confidence: 99%