Abstract
Primary dendritic cells and myeloid cell lines are used to assess the skin sensitization hazard in in vitro approaches. The aryl hydrocarbon receptor (AhR) modulates expression of CYP enzymes which play a significant role in the bioactivation of various xenobiotics. These studies revealed a strong constitutive expression of the AhR in primary human monocytes, monocyte-derived immature dendritic cells (iDC) and cord blood-derived Langerhans cells (LC). In contrast, mRNA and protein expression of AhR was hardly detectable in the cell lines THP-1 and MUTZ-3. U937 cells and MUTZ-3-derived dendritic (MUTZ-DC) or Langerhans cells (MUTZ-LC) showed about half the expression of AhR compared to iDC. Incubation of cells with the specific AhR-inducer benzo[a]anthracene resulted in an upregulation of CYP and IL-1β mRNA expression in primary monocytes and iDC. CYP1A1 but not CYP1B1 and IL-1β expression was increased by benzo[a]anthracene in these cell lines except for U937 cells. AhR-independent CYP genes were not regulated by benzo[a]anthracene. Constitutive mRNA expression of other non AhR-dependent CYP enzymes was higher in some of the cell lines compared to the corresponding primary cells. This study demonstrates significant differences in expression and regulation of phase I genes in cell lines currently used for in vitro skin sensitization hazard assessment compared to primary cells. Additional studies are required regarding the combination of cutaneous xenobiotic metabolizing enzymes and APC-sensitization for the development of valid in vitro models for skin sensitization assessment.
Highlights
Cytochrome P450 enzymes (CYP) represent a key metabolic enzyme family capable of metabolizing drugs and chemicals in hepatic and extrahepatic tissues including the skin
Monocytes express the highest level of aryl hydrocarbon receptor (AhR) (Fig. 1A) while the expression of AhR in immature dendritic cells (iDC) and in the single Langerhans cells (LC) sample was comparable (Fig. 1A,C)
MUTZ-3 and THP-1 cells showed a lower expression of AhR compared to iDC and monocytes (Fig. 1A)
Summary
Cytochrome P450 enzymes (CYP) represent a key metabolic enzyme family capable of metabolizing drugs and chemicals in hepatic and extrahepatic tissues including the skin. The induction of CYP1A1 and CYP1B1 enhances the metabolism of polycyclic aromatic hydrocarbons (PAH), benzo[a]pyrene and benzo[a]anthracene (Modi et al, 2012), which are potent carcinogens and are able to induce contact hypersensitivity (Anderson et al, 1995). Humans are exposed to PAHs and related chemicals mainly through tobacco smoking and automobile exhaust (Finlayson-Pitts and Pitts, 1997; Rubin, 2001). The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with multiple functions in adaptive metabolism (Bock and Köhle, 2009). AhR is activated by a conformational change
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