UPREGULATION OF CYP1B1, CYP3A, TAP1 AND TAP2 IN CULTURED LYMPHOCYTES FROM PATIENTS WITH PORPHYRIA CUTANEA TARDA AFTER IN VITRO-STIMULATION WITH INTERFERON ALPHA

Poblete-Gutiérrez P1, Neis MM2, Rübben A2, Merk HF2, Baron JM2, Frank J3

 

1Department of Dermatology and Allergology and Porphyria Center and Interdisciplinary Center for Clinical Research, 2Department of Dermatology and Allergology, 3Department of Dermatology and Allergology and Porphyria Center, University Clinic of the RWTH Aachen, Aachen, Germany

 

 

Porphyria cutanea tarda (PCT) is the most frequent cutaneous disorder of porphyrin-heme biosynthesis worldwide. At least two forms of PCT are currently distinguished: Sporadic/acquired (type I) PCT without family history, and familial/inherited (type II) PCT, resulting from dominantly inherited mutations in the uroporphyrinogen decarboxylase (URO-D) gene. Both types of PCT arise from decreased activity of the encoded enzyme URO-D, leading to cutaneous porphyrin deposition and photosensitization on the sun exposed areas of the skin. However, the enzymatic deficiency by itself is usually not sufficient for the development of cutaneous symptoms. Clinically overt disease rather requires the involvement of specific triggering factors. These factors are mainly alcohol, estrogens, iron and polychlorinated hydrocarbons. Interestingly, in a 63-year-old male with malignant melanoma we observed the occurrence of PCT after interferon alpha (IFN-alpha) treatment. Mutation analysis of the URO-D gene revealed a heterozygous missense mutation in this individual, indicative of type II PCT. Subsequently, we cultured lymphocytes obtained from peripheral blood of the patient and also from a second patient with clinically overt type I PCT. Lymphocytes from both patients were stimulated in vitro at different concentrations with INF-alpha and phenobarbital, a further drug known to provoke PCT. Interestingly, we observed a significant upregulation of cytochrome P450 (CYP) 1B1 and CYP3A in both individuals. Further, an upregulation of CYP 3A5 was detected in the patient with type II PCT after stimulation with phenobarbital. mRNA-expression of the transport-associated proteins (TAP) 1 and 2 was upregulated in the individual with type II PCT after stimulation with IFN-alpha proving the modulating effect of long term immunotherapy on antigen presentation. However, this effect was not observed in the patient with type I PCT who did not receive INF-alpha. Although previous data obtained in hepatocytes indicated a downregulatory effect of INF-alpha on CYP expression, our results show that it leads to an upregulation of CYP expression in other tissues. Our results suggest that cytokines like INF-alpha, commonly used in low and high dose immunotherapy, represent as yet unrecognized mediators with the potency of triggering PCT.