Role of vitamin B6 in skin health and diseases

Abstract

Vitamin B6 has been believed to be essential for skin development and maintenance. Additionally, vitamin B6 has long been considered to have an important role in amino acids metabolism as a coenzyme. Vitamin B6 deficiency has been known to be associated with dermatitis, while contact allergy to vitamin B6 is generally rare. There is accumulating evidence that dietary vitamin B6 has protective roles in cardiovascular disease and diabetes. Recent studies have further highlighted the important protective role of vitamin B6 in carcinogenesis, especially colon carcinogenesis. For skin cancer, a recent study has underlined that dietary supplemental vitamin B6 to a low vitamin B6 diet enhanced UV-irradiated skin tumorigenesis in hairless mice. However, dietary vitamin B6 caused no influence on carcinogen-induced skin tumorigenesis in mice. Topical application of vitamin B6 has been reported to exaggerate UV-irradiated skin phototoxicity. The toxic properties of irradiated vitamin B6 compounds have been also demonstrated for human fibroblasts. Thus, there is concern that excessive dose or abuse of vitamin B6 might cause adverse effect on skin health under certain conditions such as strong sunlight despite its essential roles for skin maintenance.

Full text

58 Handbook of diet, nutrition and the skin
Key facts
t
A substantial proportion of the population of USA, European countries and Japan appears not to meet
currently recommended daily intake of vitamin B6.
tVitamin B6 has an anti-dermatitis factor, and contact allergy to vitamin B6 is generally rare.
tVitamin B6 has the anti-oxidative, anti-glycation, anti-inflammation and anti-angiogenesis activities.
tVitamin B6 has protective roles against several diseases including cardiovascular diseases, diabetes, brain
diseases and colon cancer.
t
For skin cancer, higher consumption of vitamin B6 enhances UV-induced skin tumorigenesis, but not in
carcinogen-induced skin tumorigenesis.
tVitamin B6 has a phototoxic activity under UV exposure.
Summary points
t
Vitamin B6 was discovered as an anti-dermatitis factor, and has been believed to be essential for skin
development and maintenance.
tVitamin B6 inadequacy appears to be a global problem, and recently much attention has been paid to the
role of vitamin B6 in the development of certain diseases, including cardiovascular disease, diabetes and
colon cancer.
tRecent studies have underlined that higher intake of vitamin B6 enhances UV-irradiated skin tumorigenesis,
but not carcinogen induced skin tumorigenesis.
tThere is evidence that pharmacological dose of vitamin B6 causes phototoxicity under UV-irradiation.
t
Thus, it is our recommendation that under strong sunlight, higher dose or abuse of vitamin B6 for skin
maintenance should be avoided despite its essentiality for skin health.

59
4. Role of vitamin B6 in skin health and diseases
N. Kato
Laboratory of Molecular Nutrition, Graduate School of Biosphere Science, Hiroshima University,
Higashi-Hiroshima 739-8528, Japan; nkato@hiroshima-u.ac.jp
Abstract
Vitamin B6 has been believed to be essential for skin development and maintenance. Additionally,
vitamin B6 has long been considered to have an important role in amino acids metabolism as a
coenzyme. Vitamin B6 deciency has been known to be associated with dermatitis, while contact
allergy to vitamin B6 is generally rare. ere is accumulating evidence that dietary vitamin B6 has
protective roles in cardiovascular disease and diabetes. Recent studies have further highlighted
the important protective role of vitamin B6 in carcinogenesis, especially colon carcinogenesis.
For skin cancer, a recent study has underlined that dietary supplemental vitamin B6 to a low
vitamin B6 diet enhanced UV-irradiated skin tumorigenesis in hairless mice. However, dietary
vitamin B6 caused no inuence on carcinogen-induced skin tumorigenesis in mice. Topical
application of vitamin B6 has been reported to exaggerate UV-irradiated skin phototoxicity. e
toxic properties of irradiated vitamin B6 compounds have been also demonstrated for human
broblasts. us, there is concern that excessive dose or abuse of vitamin B6 might cause adverse
eect on skin health under certain conditions such as strong sunlight despite its essential roles
for skin maintenance.
Keywords: vitamin B6, dermatitis, cancer, skin, phototoxicity
V.R. Preedy (ed.), Handbook of diet, nutrition and the skin
DOI 10.3920/978-90-8686-729-5_4, © Wageningen Academic Publishers 2012
, Human Health Handbooks no. 2,

60 Handbook of diet, nutrition and the skin
N. Kato
Abbreviations
AGEs Advanced glycation endproducts
AOM Azoxymethane
DMBA Dimethylbezanthracene
PL Pyridoxal
PLP Pyridoxal 5’-phosphate
PM Pyridoxamine
PN Pyridoxine
ROS Reactive oxygen species
TBARS iobarbituric acid-reactive substances
TPA 12-O-tetradecanoylphorbol-13-acetate
UV Ultraviolet
4.1 Introduction
In 1932, Paul György discovered vitamin B6 as an anti-dermatitis factor (György and Eckardt,
1932). In the ensuing decades, vitamin B6 in the form of pyridoxal 5’-phosphate had been
discovered to serve as a coenzyme in many reactions of human intermediary metabolisms.
Tremendous advances have been made in the eld of vitamin B6 enzymology during more than
half century (Merrill and Henderson, 1987). Beyond the role of vitamin B6 as a coenzyme, recent
discovery of potential functions of vitamin B6 such as antioxidant (as radical scavenger), anti-
glycation and anti-inammation activities re-awakened interest in the protective roles of vitamin
B6 in certain diseases, including vascular disease, diabetes and cancers (Clayton, 2006). On the
other hand, recent growing evidence has suggested that excessive dose of vitamin B6 can cause
adverse eect on skin health despite its anti-dermatitis role. is review surveys the utilization
of B6 in the treatment of skin health and diseases.
4.2 B6 vitamers and their nutrition
All three forms of vitamin B6, PN, PL and PM, are precursors of an activated compound known
as PLP, which plays a vital role as the co-factor of a large number of essential enzymes in the
human body (Figure 4.1). Enzymes dependent on PLP focus a wide variety of chemical reactions
mainly involving amino acids. Vitamin B6 is obtained from various dietary sources (cereals, meat,
sh, poultry, soy and some fruits such as bananas and avocado, etc.), although bioavailability can
vary considerably. Foods contain three types of B6 vitamers, PN, PM, and PL. PN is plentiful
in plants and readily converted to other forms of vitamin B6 compounds aer absorption from
the human intestine. PLP accounts for at least 60% of the circulating vitamin B6 in humans.
Pharmacologic formulations of vitamin B6 include PN and PN hydrochloride in various dosages.

Handbook of diet, nutrition and the skin 61
4. Role of vitamin B6 in skin health and diseases
Higher intakes of vitamin B6 are required in pregnancy and lactation and possibly also in the
elderly (Merrill and Henderson, 1987). Alcohol consumption and high protein intake elevate
the requirement of vitamin B6. A substantial proportion of the population of USA, European
countries and Japan appears not to meet currently recommended daily intake. Despite the close
link of vitamin B6 with human health, vitamin B6 inadequacy is not widely recognized as a
problem. ere is little evidence that pharmacological doses of vitamin B6 have any benecial
eect. Extremely high intakes (in excess of 500 mg/day) have been reported to cause neurological
damage (Clayton, 2006).
Vitamin B6 deciency is associated with elevation in blood homocysteine, a risk factor for
cardiovascular disease, by impairing homocysteine metabolism. Low vitamin B6 status is linked
to inammation, a risk factor of cardiovascular disease (Friso et al., 2001). PN has been reported
to have a potent radical scavenger activity (Bilski et al., 2000). PM has an inhibitory activity
for glycation (Voziyan and Hudson, 2005). AGEs are marker and predictors of progression of
diabetic complications. Large doses of PM appear to be benecial for the treatment of diabetic
nephropathy.
4.3 Vitamin B6 and dermatitis
Skin lesions were the rst symptoms identied with vitamin B6 deciency in rats (György and
Eckardt, 1932). Seborrheic dermatitis was subsequently observed in vitamin B6 deciency in
humans (Prasad et al., 1983). e dermatitis caused by this vitamin deciency has been suggested
to be due to impaired collagen biosynthesis (Prasad et al., 1983; Merrill and Henderson, 1987). A
role of vitamin B6 in the anti-inammatory response might also partially relate to the dermatitis
Figure 4.1. Chemical structures of vitamin B6 compounds.
PL: pyridoxal, PN: pyridoxine, PM: pyridoxamine and PLP: pyridoxal 5’-phosphate.
HO
N
R1
R2
H3C
Vitamin B6
compound R1 R2
PL –CHO –OH
PN –CH2OH –OH
PM –CH2NH2 –OH
PLP –CHO
O
–O–P–OH
OH

62 Handbook of diet, nutrition and the skin
N. Kato
(Friso et al., 2001). PLP is important as a cofactor in the decarboxylation reactions by which
skin produces biogenic amines such as catecholamines, histamine and serotonin (Slominski
and Wortsman, 2000). Contact allergy to vitamin B6 is generally rare, and there have been a
few reports for hypersensitivity to vitamin B6 (Yoshikawa et al., 1985; Friedman et al., 1986;
Camarasa et al., 1990).
4.4 Vitamin B6 and cancers
4.4.1 Skin cancer
Vitamin B6 is important for skin development and maintenance. Vitamin B6 deciency is
associated with skin dermatitis. Additionally, vitamin B6 has been reported to have a strong
antioxidant eect (Bilski et al., 2000). erefore, adequate intake of vitamin B6 has been believed
to be essential for skin health and maintenance.
UV radiation, particularly UVB wavelengths (280-320 nm), results in an increased generation of
ROS that overwhelms the antioxidant defense mechanisms of the skin. ROS are associated with
the initiation, promotion and progression of skin cancer. Vitamin B6 has a strong antioxidant
eect like a singlet oxygen quencher (Bilski et al., 2000) and prevents lipid peroxidation (Kannan
and Jain, 2004). From these facts, vitamin B6 might be benecial for the skin exposed to UV.
us, Lu et al. (2008) have examined the eect of dietary vitamin B6 on UVB-induced skin
tumorigenesis. Surprisingly, they have found the exacerbation of UV-induced skin tumorigenesis
by dietary vitamin B6. e data of tumor incidence and tumor multiplicity indicated that dietary
supplementation of vitamin B6 to a low vitamin B6 diet enhances UV-induced skin tumorigenesis
in hairless mice treated with DMBA (Figure 4.2). In their experiment, PN hydrochloride (HCl)
was supplemented to the basal diet at the dose of 1 mg/kg (the minimum level required for
preventing the growth depression by this vitamin deciency), 7 mg/kg (the recommended level)
or 35 mg/kg. e skin levels of oxidative stress markers such as lipid peroxides (TBARS) and
protein carbonyls (a marker of protein oxidation) were unaected by dietary level of vitamin B6
(Table 4.1). Vitamin B6 has gained widespread acceptance as being nontoxic, with large doses
being given to treat various disease states. eir study indicates that compared with the low
vitamin B6 diet, UV-induced skin tumorigenesis is enhanced by the 35 mg PN HCl/kg diet,
which is far lower than any acute toxic level (>500 mg PN HCl/kg diet). is adverse eect
of dietary vitamin B6 on UV-induced tumorigenesis appears to be similar to the exacerbation
of UV-induced carcinogenesis by treatment of β-carotene (a singlet oxygen quencher). Very
recently, Kato et al. have studied the inuence of dietary level of vitamin B6 on DMBA-treated,
TPA-induced skin tumorigenesis in mice (unpublished data, 2010). ere was no signicant
dierence in the tumor incidence and number among the groups fed 1, 7 and 35 mg PN HCl/kg
diet in TPA-induced skin tumorigenesis (Table 4.2). us, a higher incidence of skin tumor with a
higher vitamin B6 intake appears to be observed in the UV-induced, but not in the TPA-induced
skin tumorigenesis. Taken together, these results suggest that an interaction between vitamin B6
and UV-radiation might be responsible for higher carcinogenic process in skin.

Handbook of diet, nutrition and the skin 63
4. Role of vitamin B6 in skin health and diseases
Vitamin B6 had been discovered as an anti-dermatitis factor, and has long been believed to
be essential for skin development and maintenance. On the basis of such information, vitamin
B6 has been oen incorporated into various supplements and skin creams for skin care and
maintenance. However, it is possible that dietary supplemental vitamin B6 potentiates UV-
induced skin tumorigenesis at the dose being far lower than acute toxic level. is raises concern
that higher dose of vitamin B6 might be harmful for the skin under strong UV exposure.
Figure 4.2. Effect of dietary level of vitamin B6 on the cumulative skin tumor multiplicity (skin tumors/mouse) in
DMBA-UV treated mice. Values from 15 mice per group are shown. *Significantly different (Pooled SEM = 0.170
and 0.134 at 17 weeks and 18 weeks, respectively, Scheffe’s multiple-range test, P<0.05). (From Lu et al., 2008:
with permission from Center for Academic Publications Japan)
Skin tumors/mouse (n)
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Wk of UVB irradiation
10 11 12 13 14 15 16 17 18
35 mg PN HCl/kg
7 mg PN HCl/kg
1 mg PN HCl/kg
*
*
**
Table 4.1. Effect of dietary vitamin B6 on skin oxidative stress markers, thiobarbituric acid-reactive substances
(TBARS) and protein carbonyls and PLP status in DMBA-UV treated hairless mice (From Lu et al. 2008: with
permission from Center for Academic Publications Japan).
Dietary pyridoxine HCl
1 mg/kg 7 mg/kg 35 mg/kg
Skin TBARS (nmol/mg protein) 2.35±0.50 1.95±0.32 1.16±0.25
Skin carbonyls (nmol/mg protein) 4.04±0.61 3.92±0.71 4.74±0.79
Skin PLP (nmol/g tissue) 2.61±0.10 2.46±0.18 2.66±0.06
Serum PLP (nmol/l) 124±8b157±10a151±7ab
The data indicate means ± SE (n=5). Means in a row not sharing a superscript letter are significantly different
(Scheffe’s multiple-rang test, P<0.05).

64 Handbook of diet, nutrition and the skin
N. Kato
4.4.2 Colon and other cancers
ere have been many epidemiological studies indicating an inverse association between vitamin
B6 status and the risk of colon cancer. Larsson et al. (2010) have recently reviewed and conducted
meta-analysis of several previous studies. eir results showed that the blood PLP levels were
inversely associated with the risk of colorectal cancer in the meta-analysis. Consistent with these
studies, Komatsu et al. (2001) strikingly demonstrated that compared with a low vitamin B6 diet,
a moderate dose of dietary vitamin B6 caused a marked reduction in colon tumorigenesis in mice
received azoxymethane. It has been suggested that the anti-colon tumor eect is mediated by
suppression in colon epithelium cell proliferation, oxidative stress, inammation and angiogenesis
(Komatsu et al., 2003).
ere have been limited studies of epidemiological studies on the relation between B6 status
and other cancers. For lung cancer, case control study and cohort study in European countries
have both indicated a signicant association between serum B6 status and incidence of the
cancer (Hartman et al., 2001; Johansson et al., 2010). ere has been controversy over the role of
vitamin B6 in breast cancer (Zhang et al., 2008, 2003) and prostate cancer (Weinstein et al., 2003;
Weinstein et al., 2006). Studies on the relation of vitamin B6 status and other cancers, including
bladder, pancreatic, ovarian, gastric, bladder, endometrical, oral cancers, etc., are sparse and
currently under intense investigation.
4.5 Vitamin B6 and phototoxicity
ere have been a few reports of photosensitivity due to PN HCl in pharmacological doses. In
1986, Friedman and coworkers (1986) reported a phototoxic reaction with pyridoxine abuse.
Murata et al. (1998) have described photosensitive dermatitis caused by PN HCl. It has been
Table 4.2. Effect of dietary vitamin B6 on the incidence (%) and number (n) of skin tumors in DMBA-TPA treated
mice.
Dietary pyridoxine HCl 7 weeks 9 weeks 11 weeks
%N %N %N
1 mg/kg 1510.75±0.10* 45 4.0±1.2 85 11.1±2.2
7 mg/kg 15 0.75±0.10 50 2.3±1.0 85 10.1±2.1
14 mg/kg 5 0.25±0.10 60 2.5±0.5 90 10.0±1.5
35 mg/kg 19 0.95±0.05 75 4.5±2.1 85 15.3±2.6
1The data indicate the percentage (%) of mice with tumors from 20 mice per group, and means ± SE (n=20) of
the number (n) of tumors per mice.

Handbook of diet, nutrition and the skin 65
4. Role of vitamin B6 in skin health and diseases
reported that vitamin B6 has a strong cytotoxic eect aer UV-irradiation in cell culture system
of human skin broblasts (Wondrak et al., 2004). ese studies suggest that UV-induced vitamin
B6 cytotoxicity is caused by toxic photoproducts resulting from irradiated vitamin B6. Wondrak
et al. (2004) have reported that the cytotoxic eects of UV-irradiated B6 vitamers include
inhibition of cell proliferation, elevation of protein photocross-linking, peptide photooxidation
and intracellular peroxide formation. e addition of several types of antioxidants do not revert
UV-irradiated PN eects, implying that ROS formation appears not to be essential for skin
phototoxicity of B6 vitamers (Wondrak et al., 2004). Although the mechanism of phototoxicity
of vitamin B6 is still unclear, the higher development of skin tumors with higher intake of vitamin
B6 mentioned above might be ascribed to the phototoxicity of vitamin B6.
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