Joan Eilstein. Metabolizing Enzymes in Human Skin. from SkinEthic TM. ADMET - Metabolism. L OREAL Advanced Research
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1 Update in the Characterization ti of Metabolizing Enzymes in Human Skin and Reconstructed t Human Skin Models from SkinEthic TM Joan Eilstein ADMET - Metabolism Predictive Methods and Models Development Department L OREAL Advanced Research 2 nd Skin metabolism Meting 213 Valbonne, France, 1-11 october 213
2 Generalities LIVER SKIN VS Main cells type Hepatocytes Keratinocytes Main functions Endogenous & Drug metabolisms Barrier function, thermoregulation Weight 2% body weight 15% body weight, 2 m 2 Characterization of the skin metabolic capabilities
3 Regulatory context REACh Chemicals characterization & 7 th Amendment to the Cosmetic Directive Non animal approaches In vitro assays development Use of reconstructed human skin models
4 Reconstructed Human Skin TYPE Normal Human Skin (NHS): Epidermis/Dermis (BIOPREDIC) Episkin TM : Reconstructed human epidermis SkinEthic TM RHE: Reconstructed human epidermis Full thickness of Episkin TM : Reconstructed human epidermis / equivalent dermis ORIGIN Mammoplasties NHK (mammoplasties) Pool of 4 5 donors Support: BPER NHK (foreskin/abdo) 1 donor/pool of 2 donors Support: Polycarbonate NHK (mammoplasties) Pool of 4 5 donors Support: Polycarbonate Comparison of metabolic capabilities between normal human skin and models
5 Develop Approach : Fluorogenic radiolabelled or UV visible absorbing substrates
6 Expression profiles of phase 1 and 2 metabolizing enzymes J Steroid Biochem Mol Biol. 29 Sep;116(3-5): Phase I (functionalisation) Phase II (conjugation)
7 Expression profiles of phase 1 and 2 metabolizing enzymes J Steroid Biochem Mol Biol. 29 Sep;116(3-5): Phase I (functionalisation) Phase II (conjugation)
8 Activity studies General procedure Dose-effect Substrate ± Inhibitor Receptor compartment Vmax 5 Substrate/Product(s) x hours, 37 C [Product] ol.mg 1.min 1 ) [ (pmo Vmax 25 2 Clearance = V max /K M Substrate/product(s) quantification Protein quantification K M 5 1 [Substrate] µm Apparent enzymatic parameters 1. Time-course study: Incubation time determination 2. Dose-effect study: Apparent enzymatic parameters K m, V max and V max /K m ratio
9 Phase I Metabolizing Enzyme Activities EROD, 7- -MFCOD & 7-BFCOD activities (pm mole.mg prot -1.6 hou urs -1 ) (~95%) a (~4%) c CYP45 (n=4) EROD 7-MFC-dealkylase 7-BFC-dealkylase (~9%) a (~65%) c (~95%) c (~95%) a (~4%) a (~85%) c TM NHS Episkin SkinEthic RHE TM (~4%) FTM TM GPx activity yl 2 propanol (pmol*m mg 1 *mn 1 ) 2 pheny GPx (n=4 ; NHS variable) 15 3 Cumene Hydropéroxyde (µm) Esterase activity -MU] (pmol.mg -1.m min -1 ) [ (mg.min.pmol ) 1/v.12.6 Esterases (n=4) Lineweaver-Burk plot /[4-MUAc] (µm -1 ) [4-MUAc] µm ADH activity [CIN-C COOH+CIN-CHO] (pmo ol.mg -1.min -1 ) 5 25 ADH (n=4) 5 ALDH (n=4) : NHS CIN-COOH activi ity [4 4-MU] (pmol.mg -1. min -1 ) 25 :: Episkin TM X : SkinEthic TM RHE ::FTM 25 5 [CIN-OH] µm 25 5 [CIN-CHO] µm Normal Human Skin vs Models: Km app and Vmax app different but V max /K m ratio equivalent
10 Phase II Metabolizing Enzyme Activities 8 GST (n=4) 5 NAT (n=4) 24 COMT (n=4) Glut tathion S-transfera ase activity [D DNPSG] (pmol.mg -1.min -1 ) [CDNB] µm N -Acetylation ac ctivity [P PAcBA] (pmol.mg -1.min -1 ) [PABA] µm COMT activity vanilic and isovanilic acid (pmo ol*mg 1 *mn 1 ) ,4 dihydroxybenzoic acid (µm) Glucuronidation ac ctivity -1 -MUG] (pmol.mg -1.mn ) [4 4 2 UGT (n=4) SULT (n=4) : NHS 4 :: Episkin TM X : SkinEthic TM RHE ::FTM 2 No SULT activity detected [ PNPS] (pmol.mg -1.m mn -1 ) [4-MU] µm 3 6 [PNP] µm Normal Human Skin vs Models: Km app and Vmax app different but V max /K m ratio equivalent
11 Metabolizing enzyme activities comparison Activity Apparent enzymatic parameters (Mean +/- SEM) NHS Episkin TM SkinEthic TM RHE FTM ES 2.1 ± ± ± ± 1. GPx 1.5 ±.6.7 ± ± ±.1 ALDH 1.6 ±.3.6 ±.1.8 ±.1.9 ±.4 UGT ± ± ± ± 1.1 V max /K m ratio GST 1. ± ± ± ±.2 NAT1.7 ±.3 1. ± ± ±.1 COMT ND 2.2 ± 2.2 ND 4.4 ± 5.5 ADH.3 ±.3.1 ±.1.2 ±.1.3 ±.1 MODEL COMPARISON PER ACTIVITY: NHS clearances are highly variables Model clearances are often similar with NHS clearances (except for ES EPIS&RHE, ADH EPIS, GPx EPIS, NAT FTM ) Apparent Vmax/Km (µl.mg protein -1.min- 1 ) Generaly models are similar to NHS in term of metabolic capabilities
12 Summary of Activities Studies ACTIVITIES Low basal expression and activity of CYP45 involved in «Drug metabolism» (!! induction!!) Glutathion peroxydase activityit was detected High esterase activity (Low affinity with the compound used as substrate ) ADH and ALDH were detected NAT activity was detected GST activity was detected UGT activity was detected Very low SULT activity except for steroid sulfation COMT activity was detected Other enzymes to be quickly tested: Phase I: FMO Phase II: COMT (in progress) Transporters COMPARISON Apparent enzymatic parameters were calculated and compared between reconstructed skin models and with normal human skin: Affinities (Km) and Maximal velocities (Vmax) are different Clearances (Vmax/Km ratio) are often similar & toxicity it
13 Conclusion SKIN IS INVOLVED IN METABOLIZING PROCESS (potential First Pass Effect) SKIN IS RATHER A DETOXIFICATION ORGAN THAN A BIO ACTIVATING ONE TOXICITY APPEARS IN SKIN WHEN: - DETOXIFICATION SYSTEMS ARE OVER EXPOSED TO TOXICANTS - REACTIVE MOLECULES ARE RELEASED IN LARGE AMOUNTS RECONSTRUCTED HUMAN SKIN MODELS ARE GOOD ENOUGH PREDICTIVE TOOLS OF SKIN METABOLISM AND TOXICITY
14 Thanks to. L OREAL Guillaume Léreaux José Cotovio Alexia Garrigues-Mazert Daniel Duché CYP45 experiments: Oroxcell SAS Normal Human Skin BIOPREDIC D. Mansuy M. Delaforges V. Luu The
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