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Background  There are unpredictable inter-individual differences in sensitivity to psoralen-UVA (PUVA) photochemotherapy, used to treat skin diseases including psoriasis. Psoralens are metabolised by cytochrome P450 enzymes (P450), and we hypothesised that variability in cutaneous P450 expression may influence PUVA sensitivity. We previously showed that P450  CYP1B1  was abundantly expressed in human skin and regulated by PUVA, and described marked inter-individual differences in cutaneous  CYP1B1  expression.    Objectives  We investigated whether  CYP1B1  made a significant contribution to 8-methoxypsoralen (8-MOP) metabolism, and whether individuality in  CYP1B1  activity influenced PUVA sensitivity.    Methods  We used  E. coli  membranes co-expressing various P450s and cytochrome P450 reductase ( CPR ) to study 8-MOP metabolism and cytotoxicity assays in  CYP1B1 -expressing mammalian cells to assess PUVA sensitivity.    Results  We showed that P450s  CYP1A1, CYP1A2, CYP1B1, CYP2A6  and  CYP2E1  influence 8-MOP metabolism. As  CYP1B1  is the most abundant P450 in human skin, we further demonstrated that: (i)  CYP1B1  interacts with 8-MOP (ii) metabolism of the  CYP1B1  substrates 7-ethoxyresorufin and 17-β-estradiol showed concentration-dependent inhibition by 8-MOP and (iii) inhibition of 7-ethoxyresorufin metabolism by 8-MOP was influenced by  CYP1B1  genotype. The influence of  CYP1B1  on PUVA cytotoxicity was further investigated in a Chinese hamster ovary cell line, stably expressing  CYP1B1  and  CPR , which was more sensitive to PUVA than control cells, suggesting that  CYP1B1  metabolises 8-MOP to a more phototoxic metabolite(s).    Conclusion  Our data therefore suggest that  CYP1B1  significantly contributes to cutaneous 8-MOP metabolism, and that individuality in  CYP1B1  expression may influence PUVA sensitivity.

Cytochrome P450 CYP1B1 Interacts with 8-Methoxypsoralen (8-MOP) and Influences Psoralen-Ultraviolet A (PUVA) Sensitivity