**4.1 Acne vulgaris (antiacne)**

Acne vulgaris is a common dermatological condition that affects physical and psychological aspects of patients [116]. Several diseases that show the presence of a certain degree of acne also relate with depression and emotional stress such as type-2 diabetes, rheumatoid arthritis, and polycystic ovarian syndrome (PCOS) [117–119]. Pathophysiology of this disease involves several key mechanisms including excessive sebum production due to hormonal and environmental conditions, alteration of fatty acids composition due to sebum metabolism by *Cutibacterium acnes*, hyperkeratinization within the follicle that clogs up the pore in the form of whitehead or blackhead comedones, inflammation induced by bacterial colonization, and malfunction of locale innate and adaptive immune system [120]. The presence of acne vulgaris is also correlated to the clinical depression in patients [116]. In this case, depression or stress can influence the regulation of sebaceous gland as the main part in sebum production [121]. Catecholamines (epinephrine and norepinephrine) as the main stress hormones also affect the growth of certain *Cutibacterium acnes* strains [122–124]. Catecholamine-treated *C. acnes* strain also can stimulate a limited but significant increase of lipid production in sebaceous

gland. However, the increase of intrinsic cytotoxicity or inflammatory potential of *C. acnes* is statistically significant [124].

Several reports exhibited that certain chromium(III) compounds have high activity in improving acne vulgaris. Initially, chromium has been used in the form of high-chromium yeast or chromium GTF (glucose tolerance factor) by consuming 400 μg chromium daily which exhibited comparable improvement in acne conditions [15]. This form of treatment, recently, is considered as a complementary and alternative medicine (CAM) for the treatment of acne vulgaris [125]. Further improvements used different chromium compounds including chromium picolinate [126, 127] and chromium salt such as chromium (III) chloride [128].

In most cases, the usage of chromium compound as antiacne is usually combined with other active compounds such as vitamins, certain minerals, and herbal medicine sources in the form of oral [129–131] or topical [128] formulation to get more effective treatment results. Application of topical formulation containing chromium (III) chloride and magnesium sulphate showed total improvement in acne vulgaris with temporal mild to moderate irritation as a side effect [128]. Oral capsule containing methionine-bound zinc complex, chromium, and vitamins also exhibited 80–100% improvements for mild to moderate acne vulgaris [131]. In another study, a combination of several nutrients with potential antiacne and anti-depressant properties (eicosapentaenoic acid, epigallocatechin-3-gallate, zinc gluconate from green tea extract, selenium, and chromium) may also improve inflammatory acne lesions and mood aspect of patients [132].

Treatment of acne vulgaris in polycystic ovary syndrome (PCOS) showed mix results. A study by Amr and Abdel-Rahim showed that using 200 μg/day oral consumption for 8 weeks has no significant improvement in acne and hirsutism [126]. In a different study, chromium supplementation by women with polycystic ovary syndrome (PCOS) in a randomized, double-blind, placebo-controlled trial exhibited that the treatment gives beneficial effects on acne and hirsutism using 1000 μg/ day oral consumption for 6 months [127]. These two studies indicated that the treatment of acne vulgaris in PCOS patients needs greater dose and longer duration.

Action mode of chromium in ameliorating acne vulgaris has not been fully elucidated yet, but there are two mechanisms proposed including (1) by decreasing serum testosterone concentration and (2) lowering the depression of patients. In the first mechanism, chromium can decrease serum testosterone level possibly due to the reduction of testicular steroidogenic enzymes activities [133]. In this case, a lower level of serum testosterone reduces sebum production in sebaceous glands [134]. The second mechanism explains that chromium as an anti-depressant [135–137] may reduce sebum production [138] and affect *C. acnes* growth in sebaceous glands [122–124]. It is clearly showed that these two mechanisms may have direct or indirect synergistic effects [139] in ameliorating skin condition with acne vulgaris.

#### **4.2 Cutaneous ageing (anti-ageing)**

Aging is a complex multifactorial process of damage accumulation that causes the deterioration of fitness [140, 141]. Aging has been the main risk factor for several deadly diseases such as cancer, cardiovascular disease, diabetes, and neurodegeneration [141]. In the skin, aging is identified by the presence of folds and wrinkles due to the declining and degradation of collagen [142], loss of elasticity [143], and decreasing of various skin functions [144]. At least, there are seven factors that may produce these clinical manifestations including passage of time, genetics, radiation such as ultraviolet and infrared radiations, lifestyle, chronic debilitating diseases, dysfunction of hormonal system, and gravitational

**131**

*Dermatologic Toxicities and Biological Activities of Chromium*

force [145]. Several mechanisms have been proposed to explain the effect of these factors on aging including oxidative stress, telomere shortening, epigenetic dysregulation, DNA damage, genetic mutation, inflammation, mitochondrial

Treatment for skin aging can be conducted through three approaches including adjusting lifestyle by routine exercise, calorie restriction, and maintaining mental health; gene therapies; and medications. Among other approaches, medication could be the simplest approach in fighting skin aging such as by using topical or systemic agents [148]. Chromium as dietary supplement (50–200 μg) has been used in preventing skin aging by controlling and regulating blood sugar and lipid levels [17]. Either in topical or systemic applications, chromium is usually combined with different vitamins and minerals to obtain optimum results based on certain parameters such as improving insulin function using chromium picolinate [149], promoting mitochondrial biogenesis and lipid metabolism using oligomannuronate-chromium(III) complexes [150], replacing or removing excess iron production using chromium(III)

dysfunction, and accumulation of glycation end product [146, 147].

chloride or chromium picolinate [151, 152], and activating telomerase [153]. Antioxidant activity of chromium may also contribute to its anti-aging properties since oxidative stress has a certain role in the damaging process. Supplementation of chromium(III) in adult male and female with type-2 diabetes mellitus minimized the increase of oxidative stress (thiobarbituric acid reactive substances—TBARS) and increased total antioxidant status [154, 155]. Several combinations have been made by formulating chromium(III) with zinc [156], niacin [157], and vitamin C/E [154] and showed a protective effect against skin damage

Antioxidant activity of chromium(III) is correlated to the dose applied as shown in several experiments. Incubation of BALB/3 T3 clone A31 cells and HepG2 cells with chromium(III) chloride concentration higher than 400 μM would induce the formation of oxidative stress, while lower optimized concentration (M = 100– 200 μM) would increase superoxide dismutase and catalase antioxidant activities [7]. In vitro study on the effect of chromium(III) and chromium(VI) on catalase activity also showed this dose-dependent activity in which treatment of cell-free

two studies clearly describe that either chromium(III) or chromium(VI) has a

Cutaneous wound is the skin defect or skin opening that is caused by external forces [159]. Formation of this wound triggers a set of complex biochemical processes to repair the damage that are called as wound healing or wound repair. In normal condition, there are five consecutive phases occurred in wound healing process including (1) homeostasis phase (immediately) through the migration of thrombocytes and formation of fibrin clot to stop the bleeding; (2) first inflammatory phase (day 1–day 6) by sensing the injury, sending the danger signal, and initializing the inflammation; (3) second inflammatory phase (day 1–day 6) through elimination the pathogens and cleaning the wound; (4) proliferation phase (day 4–day 14) through epithelialization, angiogenesis, granulation tissue formation, and collagen deposition to repair the damage and initialize the tissue remodeling process; and (5) remodeling phase (day 8–year 1) through the deposition of collagen to reach maturation of tissue structure [160–162]. Several internal and external factors have been identified to affect the wound healing process including oxygenation, infection and

certain optimum concentration to exhibit their beneficial effects.

foreign body, lifestyle, hormonal effect, age, and gender [163].

mol/L) and chromium(VI)

mol/L) separately increased the catalase activity [158]. These

*DOI: http://dx.doi.org/10.5772/intechopen.90347*

against oxidative stress.

(dose range 1–4 × 10<sup>−</sup><sup>5</sup>

catalase using chromium(III) (dose range 1–5 × 10<sup>−</sup><sup>5</sup>

**4.3 Cutaneous wound (rapid wound healing)**

#### *Dermatologic Toxicities and Biological Activities of Chromium DOI: http://dx.doi.org/10.5772/intechopen.90347*

*Trace Metals in the Environment - New Approaches and Recent Advances*

[126, 127] and chromium salt such as chromium (III) chloride [128].

inflammatory acne lesions and mood aspect of patients [132].

*C. acnes* is statistically significant [124].

gland. However, the increase of intrinsic cytotoxicity or inflammatory potential of

Several reports exhibited that certain chromium(III) compounds have high activity in improving acne vulgaris. Initially, chromium has been used in the form of high-chromium yeast or chromium GTF (glucose tolerance factor) by consuming 400 μg chromium daily which exhibited comparable improvement in acne conditions [15]. This form of treatment, recently, is considered as a complementary and alternative medicine (CAM) for the treatment of acne vulgaris [125]. Further improvements used different chromium compounds including chromium picolinate

In most cases, the usage of chromium compound as antiacne is usually combined with other active compounds such as vitamins, certain minerals, and herbal medicine sources in the form of oral [129–131] or topical [128] formulation to get more effective treatment results. Application of topical formulation containing chromium (III) chloride and magnesium sulphate showed total improvement in acne vulgaris with temporal mild to moderate irritation as a side effect [128]. Oral capsule containing methionine-bound zinc complex, chromium, and vitamins also exhibited 80–100% improvements for mild to moderate acne vulgaris [131]. In another study, a combination of several nutrients with potential antiacne and anti-depressant properties (eicosapentaenoic acid, epigallocatechin-3-gallate, zinc gluconate from green tea extract, selenium, and chromium) may also improve

Treatment of acne vulgaris in polycystic ovary syndrome (PCOS) showed mix results. A study by Amr and Abdel-Rahim showed that using 200 μg/day oral consumption for 8 weeks has no significant improvement in acne and hirsutism [126]. In a different study, chromium supplementation by women with polycystic ovary syndrome (PCOS) in a randomized, double-blind, placebo-controlled trial exhibited that the treatment gives beneficial effects on acne and hirsutism using 1000 μg/ day oral consumption for 6 months [127]. These two studies indicated that the treatment of acne vulgaris in PCOS patients needs greater dose and longer duration. Action mode of chromium in ameliorating acne vulgaris has not been fully elucidated yet, but there are two mechanisms proposed including (1) by decreasing serum testosterone concentration and (2) lowering the depression of patients. In the first mechanism, chromium can decrease serum testosterone level possibly due to the reduction of testicular steroidogenic enzymes activities [133]. In this case, a lower level of serum testosterone reduces sebum production in sebaceous glands [134]. The second mechanism explains that chromium as an anti-depressant [135–137] may reduce sebum production [138] and affect *C. acnes* growth in sebaceous glands [122–124]. It is clearly showed that these two mechanisms may have direct or indirect synergistic effects [139] in ameliorating skin condition with

Aging is a complex multifactorial process of damage accumulation that causes the deterioration of fitness [140, 141]. Aging has been the main risk factor for several deadly diseases such as cancer, cardiovascular disease, diabetes, and neurodegeneration [141]. In the skin, aging is identified by the presence of folds and wrinkles due to the declining and degradation of collagen [142], loss of elasticity [143], and decreasing of various skin functions [144]. At least, there are seven factors that may produce these clinical manifestations including passage of time, genetics, radiation such as ultraviolet and infrared radiations, lifestyle, chronic debilitating diseases, dysfunction of hormonal system, and gravitational

**130**

acne vulgaris.

**4.2 Cutaneous ageing (anti-ageing)**

force [145]. Several mechanisms have been proposed to explain the effect of these factors on aging including oxidative stress, telomere shortening, epigenetic dysregulation, DNA damage, genetic mutation, inflammation, mitochondrial dysfunction, and accumulation of glycation end product [146, 147].

Treatment for skin aging can be conducted through three approaches including adjusting lifestyle by routine exercise, calorie restriction, and maintaining mental health; gene therapies; and medications. Among other approaches, medication could be the simplest approach in fighting skin aging such as by using topical or systemic agents [148]. Chromium as dietary supplement (50–200 μg) has been used in preventing skin aging by controlling and regulating blood sugar and lipid levels [17]. Either in topical or systemic applications, chromium is usually combined with different vitamins and minerals to obtain optimum results based on certain parameters such as improving insulin function using chromium picolinate [149], promoting mitochondrial biogenesis and lipid metabolism using oligomannuronate-chromium(III) complexes [150], replacing or removing excess iron production using chromium(III) chloride or chromium picolinate [151, 152], and activating telomerase [153].

Antioxidant activity of chromium may also contribute to its anti-aging properties since oxidative stress has a certain role in the damaging process. Supplementation of chromium(III) in adult male and female with type-2 diabetes mellitus minimized the increase of oxidative stress (thiobarbituric acid reactive substances—TBARS) and increased total antioxidant status [154, 155]. Several combinations have been made by formulating chromium(III) with zinc [156], niacin [157], and vitamin C/E [154] and showed a protective effect against skin damage against oxidative stress.

Antioxidant activity of chromium(III) is correlated to the dose applied as shown in several experiments. Incubation of BALB/3 T3 clone A31 cells and HepG2 cells with chromium(III) chloride concentration higher than 400 μM would induce the formation of oxidative stress, while lower optimized concentration (M = 100– 200 μM) would increase superoxide dismutase and catalase antioxidant activities [7]. In vitro study on the effect of chromium(III) and chromium(VI) on catalase activity also showed this dose-dependent activity in which treatment of cell-free catalase using chromium(III) (dose range 1–5 × 10<sup>−</sup><sup>5</sup> mol/L) and chromium(VI) (dose range 1–4 × 10<sup>−</sup><sup>5</sup> mol/L) separately increased the catalase activity [158]. These two studies clearly describe that either chromium(III) or chromium(VI) has a certain optimum concentration to exhibit their beneficial effects.

## **4.3 Cutaneous wound (rapid wound healing)**

Cutaneous wound is the skin defect or skin opening that is caused by external forces [159]. Formation of this wound triggers a set of complex biochemical processes to repair the damage that are called as wound healing or wound repair. In normal condition, there are five consecutive phases occurred in wound healing process including (1) homeostasis phase (immediately) through the migration of thrombocytes and formation of fibrin clot to stop the bleeding; (2) first inflammatory phase (day 1–day 6) by sensing the injury, sending the danger signal, and initializing the inflammation; (3) second inflammatory phase (day 1–day 6) through elimination the pathogens and cleaning the wound; (4) proliferation phase (day 4–day 14) through epithelialization, angiogenesis, granulation tissue formation, and collagen deposition to repair the damage and initialize the tissue remodeling process; and (5) remodeling phase (day 8–year 1) through the deposition of collagen to reach maturation of tissue structure [160–162]. Several internal and external factors have been identified to affect the wound healing process including oxygenation, infection and foreign body, lifestyle, hormonal effect, age, and gender [163].

Several studies have shown that chromium(III), in a certain condition, could improve cutaneous wound either in normal or diabetic Wistar rats using a single dose of a combination of zinc(II) (1.5 mg/kg weight) and chromium(III) (0.02 mg/kg weight) [164] and C57BL6/J mice using chromium(III) chloride (80 μg/kg weight/ day) for 21 days [16]. The mechanism of this effect has not been fully elucidated yet, but it may be related to chromium(III) activity in increasing insulin sensitivity, insulin-like growth factor 1 (IGF-1) serum concentration, and protein deposition [16, 165]. In this case, high glucose concentration could inhibit proliferation and differentiation of skin keratinocytes [166] and increase the stiffness of collagen [167] which further inhibits wound healing. In healing acetic acid-induced colitis wound, chromium(III) also acted as an anti-inflammatory agent by inhibiting several inflammatory markers and downregulating pro-inflammatory cytokine genes and antioxidant by suppressing oxidative stress without any significant side effect [168].

In different situations, the use of chromium-based skin clips [169] and orthopedic implant [74] gave an adverse effect by delaying surgery wound healing process. These cases represented a hypersensitivity effect as a manifestation of systemic contact dermatitis. In vitro study using human skin keratinocyte cell line (HaCaT cells) in a medium containing chromium(III) solution (10<sup>−</sup><sup>6</sup> M) showed that chromium(III) ions can decrease wound closure rate and be further decreased when the medium was replaced with another chromium(III) ion-containing medium [170]. Chromium(III) ions also caused downregulation of toll-like receptor-2, -4, and -9 messenger ribonucleic acids (TLR-2, -4, and -9 mRNA), upregulation of matrix metalloproteinase 2 and 13, and upregulation of intercellular adhesion molecule 1 messenger ribonucleic acid (ICAM-1 mRNA) [170].

There's no exact explanation for these opposite effects. However, it may be related to the local concentration of chromium species in wound location. An enhancing effect of wound healing was obtained by applying a relatively small concentration of chromium species via oral administration. In human, for instance, there is only 2% of oral chromium(III) that will be absorbed through stomach and intestine and distributed throughout the body. In the same time, an adverse effect was obtained when local chromium concentration was high due to a particulate and soluble chromium released from the implants.
