Intradermal Concentration of Hydroquinone after Application of Hydroquinone Ointments Is Higher than Its Cytotoxic Concentration

Abstract

Ointments of the skin depigmentation agent hydroquinone (HQ) have been prepared by extemporaneous nonsterile compounding in our hospital. The HQ ointments were highly effective in the treatment of various types of skin pigmentations; however, various problems have emerged including chromatic aberration of the ointments, a relatively large variability of efficacy, and mild topical side effects including irritation. In this paper, the cytotoxicity of HQ was assessed in vitro using rat skin fibroblasts as the concentration with 50% survival after 24 h exposure to be 16.5 microM. The intradermal concentrations at 2 h after application of the HQ ointments was also estimated to be 358 mM and 51.7 mM in stratum corneum and viable tissue (viable epidermis+dermis), respectively, by an in vitro rat skin permeation study with rat full-thickness abdominal skin and Franz-type diffusion cells. It was demonstrated that the intradermal concentration of HQ was much higher than that eliciting cytotoxicity, suggesting that the topical side effects after application of HQ ointment were due to the cytotoxicity of HQ.

Evaluation of the efficacy of cysteamine 5% cream in the treatment of epidermal melasma: a randomized double-blind placebo-controlled trial

“…30,31 The cytotoxic and mutagenic potentials of hydroquinone have caused the drug regulatory authorities of several countries to ban the use of this compound as a depigmenting agent. The cytotoxicity of hydroquinone is not specific for melanocytes, and other epidermal cells, such as keratinocytes, may also be affected.…”

Involvement of Transient Receptor Potential Cation Channel Member A1 activation in the irritation and pain response elicited by skin-lightening reagent hydroquinone

“…Furthermore, our in vivo studies demonstrated that intraplantar injection of HQ at a concentration range of 1 to 30 mM can readily produce both acute pain and persistent mechanical hyperalgesia in mice. This concentration range is much lower than the concentration of HQ found in stratum corneum and epidermis plus dermis tissue (358 and 51.7 mM, respectively) when 5% clinically used HQ ointment is applied on the skin 26 . Therefore, it is quite likely that topically applied HQ ointment in patients, containing much higher amounts of HQ, will activate TRPA1 and cause irritation and pain.…”

“…A previous study investigated the intradermal concentration of clinically used HQ (5.0%) after its permeation using rat skin 26 . In that study, it was reported that the intradermal concentrations at 2 h after application of the HQ ointments were 358 mM in stratum corneum and 51.7 mM in epidermis plus dermis tissue 26 .…”

“…A previous study investigated the intradermal concentration of clinically used HQ (5.0%) after its permeation using rat skin 26 . In that study, it was reported that the intradermal concentrations at 2 h after application of the HQ ointments were 358 mM in stratum corneum and 51.7 mM in epidermis plus dermis tissue 26 . In the present study, we found that HQ can robustly activate TRPA1 currents in HEK 293 cells at concentrations as low as 10 μM and the estimated EC 50 by Ca 2+ imaging is 17.1 μM, which is far less than the concentration of HQ detected in the skin treated with a clinical ointment.…”

Topical Methimazole as a New Treatment for Postinflammatory Hyperpigmentation: Report of the First Case

“…In low concentrations (<10 µ M ), HQ shows a melanogenesis-inhibiting effect, while in higher concentrations it mainly acts as a melanocytotoxic agent [1]. The depigmenting effect of HQ products on human skin, however, is perhaps solely due to its melanocytotoxic potential, as the concentration of HQ delivered into the dermis by such products is several folds higher than the dosage required for its cytotoxic effects [4]. The cytotoxicity of HQ is not highly specific for melanocytes, and other cells, such as keratinocytes, can also be affected [1, 5].…”