Potential for metabolism locally in the skin of dermally absorbed compounds

2008 ◽  
Vol 27 (4) ◽  
pp. 277-280 ◽  
Author(s):  
FM Williams
Keyword(s):  
Cellular Localization ◽  
Skin Surface ◽  
Dermal Absorption ◽  
In Vivo Studies ◽  
Metabolizing Enzymes ◽  
Diffusion Systems ◽  
Butoxyacetic Acid ◽  
Local Metabolism ◽  
Short Term Culture

Dermally absorbed chemicals can be locally metabolized in the skin during absorption but it is difficult to distinguish this metabolism from liver metabolism by biological monitoring in vivo. Studies with sub-cellular fractions have showed the presence of metabolizing enzymes in the skin but with loss of cellular localization. Studies in HaCat cells in culture maintain cellular localization and in skin, in short-term culture, the chemical can be applied to the skin surface and metabolism during absorption can be monitored. Flow though diffusion systems with tissue culture medium as receptor fluid have maintained the viability of skin and supported metabolism, but dilution of the metabolites in the receptor fluid has limited detection. This article uses data derived by a range of techniques from the Newcastle laboratory to discuss the importance of local metabolism in the skin of butoxyethanol to butoxyacetic acid and parabens to p-hydroxybenzoic acid during dermal absorption, following application to the skin surface.

Enhanced xenobiotic transporter expression in normal teleost hepatocytes: response to environmental and chemotherapeutic toxins

2001 ◽  
Vol 204 (2) ◽  
pp. 217-227
Author(s):  
J.A. Albertus ◽  
R.O. Laine
Keyword(s):  
Mammalian Cells ◽  
Cellular Localization ◽  
Fundulus Heteroclitus ◽  
Environmental Pollutants ◽  
Human Tumor ◽  
Aquatic Organisms ◽  
In Vivo Studies ◽  
Multixenobiotic Resistance

Many aquatic organisms are resistant to environmental pollutants, probably because their inherent multi-drug-resistant protein extrusion pump (pgp) can be co-opted to handle man-made pollutants. This mechanism of multixenobiotic resistance is similar to the mechanism of multidrug resistance exhibited in chemotherapy-resistant human tumor cells. In the present study, a variety of techniques were used to characterize this toxin defense system in killifish (Fundulus heteroclitus) hepatocytes. The cellular localization and activity of the putative drug efflux system were evaluated. In addition, in vitro and in vivo studies were used to examine the range of expression of this putative drug transporter in the presence of environmental and chemotherapeutic toxins. The broad range of pgp expression generally observed in transformed mammalian cells was found in normal cells of our teleost model. Our findings suggest that the expression of the pgp gene in the killifish could be an excellent indicator of toxin levels or stressors in the environment.

scholarly journals Swertiamarin Contributes to Glucose Homeostasis via Inhibition of Carbohydrate Metabolizing Enzymes

2017 ◽  
Vol 16 (4) ◽  
pp. 125 ◽  
Author(s):  
Javed Ahamad ◽  
Naila Hassan ◽  
Saima Amin ◽  
Showkat R. Mir
Keyword(s):  
Blood Glucose ◽  
Glucose Homeostasis ◽  
In Vivo Studies ◽  
Metabolizing Enzymes ◽  
Treatment Groups ◽  
Whole Plant ◽  
Peak Blood ◽  
Peak Blood Glucose

<strong>Objective:</strong> Swertiamarin is a common secoiridoid found among the members of Gentianaceae. The present study aimed to establish the effectiveness of swertiamarin in achieving glucose homeostasis via inhibition of carbohydrate metabolizing enzymes by in-vitro and in-vivo studies. <strong>Materials and methods:</strong> Swertiamarin was obtained from dried whole plant samples of <em>Enicostemma littorale</em> Blume chromatographic fractionation over the silica gel column. Its effect on carbohydrate metabolizing enzymes viz., α-amylase and α-glucosidase were evaluated at 0.15 to 10 mg/mL in-vitro. The results were supplemented by anti-hyperglycemic studies in carbohydrate challenged mice pretreated with swertiamarin at a dose of 20 mg/kg body weight orally. <strong>Results:</strong> Swertiamarin was effective in inhibiting α-amylase and α-glucosidase with IC<em>50</em> values of 1.29±0.25 mg/mL and 0.84±0.11 mg/mL, respectively. The studies in starch and sucrose challenged mice showed that swertiamarin effectively restricted the increase in the peak blood glucose level (BGL). The increase in peak BGL was 49 mg/dL and 57 mg/dL only in the treatment groups compared to 70 mg/dL and 80 mg/dL in untreated groups after 30 min in starch and sucrose-fed mice, respectively. Acarbose (10 mg/kg b.w.) also produced significant (p&lt;0.01) blood glucose lowering response in both the models. <strong>Conclusion:</strong> Swertiamarin was effective in the achieving stricter glycemic control in carbohydrate challenged mice through the inhibition of carbohydrate metabolizing enzymes.

Use of Percutaneous Absorption Data in Risk Assessment

1989 ◽  
Vol 8 (5) ◽  
pp. 815-827 ◽  
Author(s):  
C. A. Franklin ◽  
D. A. Somers ◽  
I. Chu
Keyword(s):  
Risk Assessment ◽  
Percutaneous Absorption ◽  
Dermal Absorption ◽  
In Vivo Studies ◽  
Absorption Data ◽  
Regulatory Decision ◽  
Dermal Penetration ◽  
High Doses

Assessment of risks to humans associated with the use of chemicals requires knowledge of the hazard (toxicity) of the chemical and level of human exposure. Hazard assessment is often based on animal bioassays and quantitative exposure estimates of dermal exposure obtained from studies monitoring workers. Because human skin is an effective barrier to many chemicals, it cannot be assumed that the deposited dose is equivalent to the systemic dose. However, an estimate of systemic dose may be derived by multiplying the deposited dose by the percentage of percutaneous uptake. This correction can have major impact on the regulatory decision, because the adjusted dose used in the risk calculation may be reduced significantly, especially at high doses, when the uptake is not linearly proportional to the exposure. It is therefore important that the dermal absorption value be accurate. As outlined in this paper, numerous factors can affect percutaneous absorption. Nevertheless, many regulatory agencies will consider the use of percutaneous absorption data derived from in vivo studies to adjust the dermally deposited dose to that delivered systemically. Numerous issues must be resolved before in vitro dermal penetration studies can be used for risk assessment.

Efficacy of topical phenol decontamination strategies on severity of acute phenol chemical burns and dermal absorption: in vitro and in vivo studies in pig skin

2001 ◽  
Vol 17 (4) ◽  
pp. 95-104 ◽  
Author(s):  
Nancy A Monteiro-Riviere ◽  
Alfred O Inman ◽  
Hilary Jackson ◽  
Brendan Dunn ◽  
Stephen Dimond
Keyword(s):  
Dermal Absorption ◽  
In Vivo Studies ◽  
Chemical Burns ◽  
Pig Skin

scholarly journals The Multiple Roles of Sphingomyelin in Parkinson’s Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1311
Author(s):  
Paola Signorelli ◽  
Carmela Conte ◽  
Elisabetta Albi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nerve Impulse ◽  
In Vivo Studies ◽  
Metabolizing Enzymes ◽  
Molecular Alterations ◽  
Receptor Localization ◽  
Genetic Risks

Advances over the past decade have improved our understanding of the role of sphingolipid in the onset and progression of Parkinson’s disease. Much attention has been paid to ceramide derived molecules, especially glucocerebroside, and little on sphingomyelin, a critical molecule for brain physiopathology. Sphingomyelin has been proposed to be involved in PD due to its presence in the myelin sheath and for its role in nerve impulse transmission, in presynaptic plasticity, and in neurotransmitter receptor localization. The analysis of sphingomyelin-metabolizing enzymes, the development of specific inhibitors, and advanced mass spectrometry have all provided insight into the signaling mechanisms of sphingomyelin and its implications in Parkinson’s disease. This review describes in vitro and in vivo studies with often conflicting results. We focus on the synthesis and degradation enzymes of sphingomyelin, highlighting the genetic risks and the molecular alterations associated with Parkinson’s disease.

A Physiologically Based Mathematical Model of Dermal Absorption in Man

1994 ◽  
Vol 13 (1) ◽  
pp. 51-60 ◽  
Author(s):  
T.R. Auton ◽  
D.R. Westhead ◽  
B.H. Woollen ◽  
R.C. Scott ◽  
M.F. Wilks
Keyword(s):  
Mathematical Model ◽  
Layer Structure ◽  
Quantitative Description ◽  
Skin Surface ◽  
Dermal Absorption ◽  
Physiologically Based ◽  
Applied Dose ◽  
Parameter Values

A sound understanding of the mechanisms determining percutaneous absorption is necessary for toxicological risk assessment of chemicals contacting the skin. As part of a programme investigating these mechanisms we have developed a physiologically based mathematical model. The structure of the model parallels the multi-layer structure of the skin, with separate surface, stratum corneum and viable tissue layers. It simulates the effects of partitioning and diffusive transport between the sub-layers, and metabolism in the viable epidermis. In addition the model describes removal processes on the surface of the skin, including the effects of washing and desquamation, and rubbing off onto clothing. This model is applied to data on the penetration of the herbicide fluazifop-butyl through human skin in vivo and in vitro. Part of this dataset is used to estimate unknown model parameter values and the remainder is used to provide a partial validation of the model. Only a small fraction of the applied dose was absorbed through the skin; most of it was removed by washing or onto clothing. The model provides a quantitative description of these loss processes on the skin surface.

Absorption, Metabolism, Distribution, and Excretion of Letermovir

2021 ◽  
Vol 22 ◽  
Author(s):  
Karsten Menzel ◽  
Prajakti Kothare ◽  
Jacqueline B. McCrea ◽  
Xiaoyan Chu ◽  
Dirk Kropeit
Keyword(s):  
The Body ◽  
In Vivo Studies ◽  
Cell Transplant ◽  
Glycoprotein P ◽  
Metabolizing Enzymes ◽  
Hematopoietic Stem ◽  
Regulatory Guidance ◽  
Adme Study

Background: Letermovir is approved for prophylaxis of cytomegalovirus infection and disease in cytomegalovirus-seropositive hematopoietic stem-cell transplant (HSCT) recipients. Objective: HSCT recipients are required to take many drugs concomitantly. The pharmacokinetics, absorption, distribution, metabolism, and excretion of letermovir and its potential to inhibit metabolizing enzymes and transporters In vitro were investigated to inform on the potential for drug‒drug interactions (DDIs). Methods: A combination of in vitro and in vivo studies described the absorption, distribution, metabolism, and routes of elimination of letermovir, as well as the enzymes and transporters involved in these processes. The effect of letermovir to inhibit and induce metabolizing enzymes and transporters were evaluated In vitro and its victim and perpetrator DDI potentials were predicted by applying the regulatory guidance for DDI assessment. Results: Letermovir was a substrate of CYP3A4/5 and UGT1A1/3 in vitro. Letermovir showed concentration-dependent uptake into organic anionic transporting polypeptide (OATP)1B1/3-transfected cells and was a substrate of P-glycoprotein (P-gp). In a human ADME study, letermovir was primarily recovered as unchanged drug and minor amounts of a direct glucuronide in feces. Based on the metabolic pathway profiling of letermovir, there were few oxidative metabolites in human matrix. Letermovir inhibited CYP2B6, CYP2C8, CYP3A, and UGT1A1 in vitro, and induced CYP3A4 and CYP2B6 in hepatocytes. Letermovir also inhibited OATP1B1/3, OATP2B1, OAT3, OCT2, BCRP, BSEP, and P-gp. Conclusion: The body of work presented in this manuscript informed on the potential for DDIs when letermovir is administered both intravenously and orally in HSCT recipients.

Gene regulation by Sp1 and Sp3

2004 ◽  
Vol 82 (4) ◽  
pp. 460-471 ◽  
Author(s):  
Lin Li ◽  
Shihua He ◽  
Jian-Min Sun ◽  
James R Davie
Keyword(s):  
Gene Regulation ◽  
Transcription Factors ◽  
Dna Binding ◽  
Mammalian Cells ◽  
Cellular Localization ◽  
Target Genes ◽  
In Vivo Studies ◽  
Binding Domains

The Sp family of transcription factors is united by a particular combination of three conserved Cys2His2 zinc fingers that form the sequence-specific DNA-binding domain. Within the Sp family of transcription factors, Sp1 and Sp3 are ubiquitously expressed in mammalian cells. They can bind and act through GC boxes to regulate gene expression of multiple target genes. Although Sp1 and Sp3 have similar structures and high homology in their DNA binding domains, in vitro and in vivo studies reveal that these transcription factors have strikingly different functions. Sp1 and Sp3 are able to enhance or repress promoter activity. Regulation of the transcriptional activity of Sp1 and Sp3 occurs largely at the post-translational level. In this review, we focus on the roles of Sp1 and Sp3 in the regulation of gene expression.Key words: Sp1, Sp3, gene regulation, sub-cellular localization.

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