Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
[PURPOSE] Vemurafenib, a BRAF inhibitor, has been reported to cause adverse reactions such as acne-like rash and xeroderma in the skin. Since acne-like rash and xeroderma have been associated with the dysfunction of sebaceous glands, vemurafenib administrated may affect the sebaceous glands. In this study, we investigated the molecular mechanisms of sebum production by vemurafenib in hamster sebocytes. [METHODS] The sebum production and accumulation were analyzed by Nile red and Oil red O staining, respectively. The expression of SCD-1 and DGAT-1, which are pivotal enzymes in the sebum production, and perilipin 1, a lipid-droplet-formation factor, were evaluated by RT-PCR. The level of ERK phosphorylation was measured by Western blotting. [RESULTS] Vemurafenib enhanced the insulin-augmented sebum production, whereas suppressed the sebum production increased by 5α-dihydrotestosterone (DHT) or progesterone (P4) in hamster sebocytes. In addition, the gene expression of SCD-1, DGAT-1, and perilipin 1 was similarly enhanced and suppressed by vemurafenib in the insulin- and the DHT- or P4-treated cells, respectively. Furthermore, vemurafenib was found to increase ERK phosphorylation. Interestingly, the vemurafenib-induced ERK phosphorylation was strongly augmented in hamster sebocytes treated with DHT or P4. [DISCUSSION] Our findings suggest that the activation of MAPK pathway by vemurafenib is modulated in response to endogenous factors that augment sebum production. Thus, the level of activation of the ERK pathway in sebaceous glands may regulate the vemurafenib-dependent bidirectional adverse reactions in the skin.
