Melanin synthesis is regulated by the rate-limiting enzyme, tyrosinase, a membrane-bound copper-containing glycoprotein, which initiates the biosynthetic pathway of melanin by catalyzing the hydroxylation of tyrosine to DOPA. Since subsequent reactions in the melanin synthetic pathway, e.g., the conversion of DOPA to DOPAquinone, as well as other non-enzymatic reactions, are oxidative reactions, antioxidants such as ascorbic acid, are effective inhibitors of melanin synthesis. Ascorbic acid and its derivatives are the most popular skin lightening QDs that have ever been used in Japan.

Examples of ascorbic acid derivatives are magnesium L-ascorbic acid 2-phosphate (QD approval was obtained by the Takeda Pharmaceutical Company Limited in 1988), sodium L-ascorbic acid 2-phosphate, L-ascorbic acid 2-glucoside (obtained by Shiseido Co., Ltd. and Kaminomoto Co., Ltd. in 1994), and L-ascorbic acid ethyl ester (obtained by Shiseido Co., Ltd. in 2005). Although the inhibitory mechanism of skin lightening by L-ascorbic acid ethyl ester is to prevent polymerization of melanin monomers involved in the immediate pigment darkening of the skin induced by ultraviolet light A (UVA) (320–400 nm) [1,2], the inhibitory mechanisms of melanin synthesis by ascorbic acid and its other derivatives are mainly antioxidative in nature. L-Ascorbic acid 2-glucoside has been shown to maintain prolonged biological activity of ascorbic acid longer than sodium L-ascorbic acid 2-phosphate, a conventional ascorbic acid [3]. In clinical trials, a 10% magnesium L-ascorbic acid 2-phosphate-containing formulation was shown to be effective for reducing melasma and age spots [4]. A 2% L-ascorbic acid 2-glucoside-containing cream was shown to accelerate the disappearance of ultraviolet light B (UVB) (280–320 nm)—induced hyperpigmentation of the skin [5].

Placental extracts have long been used as an active ingredient for skin lightening QDs, together with ascorbic acid and its derivatives. Previously, a bovine-derived placental extract was the primary commercial source. However, swine-derived placental extracts are now used because of concern over mad cow disease. Various amino acids and minerals are at high concentrations in placental extracts, and the efficient inhibition of melanin synthesis and the enhancement of melanin removal from the skin, due to increased epidermal turnover have been reported [6,7]. Interestingly, although placental extract has a strong history of use to decrease hyperpigmentation, it has also been shown to increase melanogenesis. The lipid fraction of human placental extract was reported to increase melanin synthesis via the enhancement of tyrosinase gene expression [8].

Kojic acid, a pyrone derivative obtained from the fermentation process of Japanese liquor, is known to have an antibacterial activity. Kojic acid was shown to inhibit the activity of tyrosinase by chelating copper atoms in its active site [9]. In clinical trials, a 1% kojic acid-containing formulation was shown to be effective for treating hyperpigmentary disorders, such as melasma, post-inflammatory hyperpigmentation, age spots, and freckles [10].

The MHLW in March, 2003 notified suppliers of kojic acid to delay manufacture or import because of caution about possible carcinogenic effects [11]. However, after revaluation in November, 2005, kojic acid is now accepted to be safe as a cosmetic ingredient, and continues to be used as a skin lightening QD [12].

Arbutin, a naturally occurring β-D-glucopyranoside derivative of hydroquinone, is found in cowberry leaves, and inhibits tyrosinase activity competitively, but at non-cytotoxic concentrations in cultured melanocytes [13]. A 3% arbutin-containing formulation was shown to be effective for treating hyperpigmentary disorders, such as melasma [14].

Ellagic acid is a naturally occurring polyphenol found in a variety of plants, such as strawberries, geraniums, and green tea. The inhibitory effect of ellagic acid on melanin synthesis is similar to kojic acid, i.e., ellagic acid inhibits tyrosinase activity by chelating copper atoms in its active site [15]. A 0.5% ellagic acid-containing cream was shown to be effective for treating UVB-induced hyperpigmentation of the skin [16].

Chamomilla extract has been used as a traditional anti-inflammatory agent, and is the only one so far, in Japan, that has been approved as a skin lightening QD from botanical extracts. It has been shown that keratinocytes secrete endothelin-1, a type of inflammatory cytokine, which activates melanocytes when UV is irradiated on the epidermis [17]. Chamomilla extracts have been shown to act as an antagonist for endothelin-receptor binding, which mediates cell-to-cell signaling between keratinocytes and melanocytes. This antagonism leads to the inhibition of melanin synthesis in melanocytes [18]. Until then, all earlier skin lightening QDs had been developed to inhibit tyrosinase activity. In contrast, the chamomilla extract is a unique QD focused on affecting the keratinocytes that surround melanocytes. A 0.5% chamomilla extract-containing cream was shown to be effective for treating UVB-induced hyperpigmentation of the skin [19,20].

Rucinol^® was selected by screening synthetic resorcinol derivatives that can elicit strong competitive inhibition of tyrosinase activity. Melanin synthesis is catalyzed by tyrosinase, together with tyrosinase-related proteins (TRP) −1 and −2, and Rucinol^® has been shown to inhibit melanin synthesis in cultured mouse melanocytes via direct inhibition not only of tyrosinase activity [21], but also of TRP-1 activity [22]. A 0.3% Rucinol^®-containing lotion was shown to be effective for treating hyperpigmentary disorders, such as melasma [22].

Linoleic acid is an unsaturated fatty acid (C18:2) derived from hydrolyzed botanical oils, such as safflower, and is a major component of biological cell membranes. Tyrosinase is degraded endogenously in melanocytes [23], and linoleic acid has been shown to accelerate tyrosinase degradation, and to decrease tyrosinase levels. These actions lead to the down-regulation of melanin synthesis [24]. In clinical trials, topical application of a 0.1% linoleic acid-containing liposomal formulation has been shown to be effective for treating melasma [25] and to lighten UVB-induced hyperpigmentation of the skin [26,27].

Tranexamic acid has been used as a traditional hemostatic medicine, and is known as an oral medicine for treating melasma [28]. Plasmin, a kind of protease in the blood serum, functions to enhance the intracellular release of arachidonic acid, a precursor of prostanoid [29], and also to elevate alpha-melanocyte stimulating hormone processed from pro-opiomelanocortin [30]. Both arachidonic acid and alpha-melanocyte stimulating hormone can activate melanin synthesis by melanocytes. Therefore, the anti-plasmin activity of tranexamic acid is thought to play a role in its topical effectiveness for treating melasma.

The inhibitory mechanism of 4MSK on melanin synthesis was shown to be the competitive inhibition of tyrosinase activity. This mechanism is similar to those of arbutin and Rucinol^®.

Adenosine monophosphate has the potency to increase the amount of intracellular glucose uptake, which is necessary for the biosynthesis of adenosine triphosphate, a source of intracellular energy. Therefore, adenosine monophosphate disodium salt accelerates epidermal turnover due to the elevated intracellular energy metabolism, which leads to the excretion of melanin from the skin, i.e., adenosine monophosphate prevents the accumulation of melanin in the skin [31]. A 3% adenosine monophosphate disodium salt-containing formulation was shown to be effective for treating hyperpigmentary disorders, such as melasma [31].

Magnolignan^® is a biphenyl compound and a kind of polyphenol that has a structure similar to the magnolol and honokiol of Magnolia obovata. Tyrosinase is known to mature due to its glycosylation in the endoplasmic reticulum (ER) and Golgi apparatus; Magnolignan^® inhibits the maturation of tyrosinase, which leads to decreased melanin synthesis [32]. A 0.5% Magnolignan^®-containing formulation was shown to be effective for treating UVB-induced hyperpigmentation of the skin [33] and is also effective in treating hyperpigmentary disorders, such as melasma and senile lentigo [34].

4-HPB is a phenol compound found in extracts of White Birch and Nikko Maple. The inhibitory mechanism of 4-HPB on melanin synthesis was shown to be due to its competitive inhibition of tyrosinase activity.

The effect of tranexamic acid cetyl ester hydrochloride in treating hyperpigmentary disorders is due to the inhibition of UVB-induced inflammation, which leads to the quiescence of active melanocytes. This mechanism is similar to those of chamomilla extract and tranexamic acid.