title: Photobinding of 8-methoxypsoralen, 4,6,4'-trimethylangelicin and chlorpromazine to Wistar rat epidermal biomacromolecules in vivo.
abstract: Photoinduced binding of drugs to endogenous biomacromolecules may cause both toxic and therapeutic effects. For example, photobinding of certain phenothiazines to biomolecules possibly underlies their phototoxic and photoallergic potential, whereas photobinding of furocoumarins to epidermal DNA is held responsible for their advantageous effects in the photochemotherapy of psoriasis. Usually, the in vitro photobinding of drugs is investigated. However, under in vivo conditions, the metabolism and distribution of the drug and the light absorption by endogenous compounds will significantly affect the photobinding of drugs to biomolecules. Therefore, in the present study, the photobinding of 8-methoxypsoralen (8-MOP), 4,6,4'-trimethylangelicin (TMA) (two therapeutically used furocoumarins) and chlorpromazine (CPZ) (a member of the phenothiazines) was investigated in vivo. The compounds were applied topically on the shaven skin of Wistar rats; one group was exposed to UVA and the other was kept in a dimly lit environment. Immediately, and at certain time intervals after UVA exposure, members of the two groups were sacrificed. By separating epidermal lipids, DNA/RNA and proteins by a selective extraction method, irreversible binding of 8-MOP, TMA or CPZ to each of these biomacromolecules was determined. In contrast with in vitro experiments, photobinding of CPZ to epidermal DNA/RNA was not found in vivo; apparently the bioavailability in the nucleus is very low. Compared with TMA, 8-MOP was observed to bind more extensively to epidermal DNA/RNA (again in contrast with findings from in vitro experiments) and proteins, but less extensively to lipids. The rates of removal of photobound 8-MOP and TMA were comparable. Photobound CPZ was more slowly removed from epidermal proteins and lipids than the furocoumarins. The observed in vivo photobinding is discussed with respect to the UVA-induced (side) effects of these drugs.
authors.affiliation: Division of Medicinal Chemistry, University of Leiden, The Netherlands.
authors.forename: S A
authors.initials: SA
authors.lastname: Schoonderwoerd
authors.forename: G M
authors.initials: GM
authors.lastname: Beijersbergen van Henegouwen
authors.forename: C C
authors.initials: CC
authors.lastname: Persons
authors.forename: S
authors.initials: S
authors.lastname: Caffieri
authors.forename: F
authors.initials: F
authors.lastname: Dall'Acqua
mesh_terms: D000818:Animals; D002746:Chlorpromazine / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism / Q000528:radiation effects*; D005260:Female; D011564:Furocoumarins / Q000378:metabolism*; D050356:Lipid Metabolism; D008730:Methoxsalen / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014466:Ultraviolet Rays
chemical_list: D011564:Furocoumarins; D011506:Proteins; D011838:Radiation-Sensitizing Agents; D012313:RNA; D004247:DNA; C041621:4,4',6-trimethylangelicin; D002746:Chlorpromazine; D008730:Methoxsalen