Importance of UDP-glucuronosyltransferase 1A1 expression in skin and its induction by UVB in neonatal hyperbilirubinemia.
UDP-glucuronosyltransferase (UGT) 1A1 is the sole enzyme that can metabolize bilirubin. Human infants physiologically develop hyperbilirubinemia as the result of inadequate expression of UGT1A1 in the liver. Although phototherapy using blue light is effective in preventing jaundice, sunlight has also been suggested, but without conclusive evidence, to reduce serum bilirubin levels. We investigated the mRNA expression pattern of human UGT1A1 in human skin, human skin keratinocyte (HaCaT) cells, and skin of humanized UGT1 mice. The effects of UVB irradiation on the expression of UGT1A1 in the HaCaT cells were also examined. Multiple UGT1A isoforms, including UGT1A1, were expressed in human skin and HaCaT cells. When HaCaT cells were treated with UVB-exposed tryptophan, UGT1A1 mRNA and activity were significantly induced. Treatment of the HaCaT cells with 6-formylindolo[3,2-b]carbazole, which is one of the tryptophan derivatives formed by UVB, resulted in an induction of UGT1A1 mRNA and activity. In neonates, the expression of UGT1A1 was greater in the skin; in adults, UGT1A1 was expressed mainly in the liver. Treatment of humanized UGT1 mice with UVB resulted in a reduction of serum bilirubin levels, along with increased UGT1A1 expression and activity in the skin. Our data revealed a protective role of UGT1A1 expressed in the skin against neonatal hyperbilirubinemia. Sunlight, a natural and free source of light, makes it possible to treat neonatal jaundice while allowing mothers to breast-feed neonates.
School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan (K.S., M.K., E.K., T.I., S.T., T.N., R.F.); and Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, California (R.H.T.).
Kyohei
K
Sumida
Makiko
M
Kawana
Emi
E
Kouno
Tomoo
T
Itoh
Shuhei
S
Takano
Tomoya
T
Narawa
Robert H
RH
Tukey
Ryoichi
R
Fujiwara
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000528:radiation effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D051556:Hyperbilirubinemia, Neonatal / Q000201:enzymology / Q000628:therapy*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010789:Phototherapy; D012867:Skin / Q000201:enzymology*; D014364:Tryptophan / Q000528:radiation effects; D014466:Ultraviolet Rays; D000099148:UGT1A1 Enzyme
D002227:Carbazoles; D019363:Cytochrome P-450 CYP1A1; D004958:Estradiol; D014453:Glucuronosyltransferase; D014364:Tryptophan; D000099148:UGT1A1 Enzyme; C111855:6-formylindolo(3,2-b)carbazole; C025482:estradiol-3-glucuronide; C454320:UDP-glucuronosyltransferase, UGT1A8