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484 / CHAPTER 45H 3 CH 3 CH 3 CH 3 CCH 3CH 3CH 3CH 3 CH 3CH 3CH 3 H 3 CCH 3CH 3CH 3 H 3 CCH 3CH 3CHH 3 C CH 3 CH 33CH 3PhotorhodopsinCH 2 OHCH 3 H 3 CHC=NRhodopsin (visual purple)Conformational changes in proteinLIGHTH 3 CCH 3CH 310 -15 sec45 psecBathorhodopsin30 nsecLumirhodopsin75 µsecMetarhodopsin I10 msecMetarhodopsin IIminutesMetarhodopsin IIIFigure 45–2.GDPGTPCH 3 CH 3CH 2 OHHC=OC=OH 2 NLysine residuein opsin NHC=NAll-trans-retinol11-cis-RetinolcGMPNa+channel openHC=O11-cis-RetinaldehydeInactiveC=Otamin, and therefore there is further impairment of immuneresponses.Vitamin A Is Toxic in ExcessThere is only a limited capacity to metabolize vitaminA, and excessive intakes lead to accumulation beyondthe capacity of binding proteins, so that unbound vitaminA causes tissue damage. Symptoms of toxicity affectthe central nervous system (headache, nausea,NHAll-trans-retinaldehyde + opsinC=ONHTransducin-GTPTransducin-GDP5'GMP+Na channel closedActivephosphodiesteraseThe role of retinaldehyde in vision.P iataxia, and anorexia, all associated with increased cerebrospinalfluid pressure), the liver (hepatomegaly withhistologic changes and hyperlipidemia), calcium homeostasis(thickening of the long bones, hypercalcemiaand calcification of soft tissues), and the skin (excessivedryness, desquamation, and alopecia).VITAMIN D IS REALLY A HORMONEVitamin D is not strictly a vitamin since it can be synthesizedin the skin, and under most conditions that isits major source. Only when sunlight is inadequate is adietary source required. The main function of vitaminD is in the regulation of calcium absorption and homeostasis;most of its actions are mediated by wayof nuclear receptors that regulate gene expression.Deficiency—leading to rickets in children and osteomalaciain adults—continues to be a problem in northernlatitudes, where sunlight exposure is poor.Vitamin D Is Synthesized in the Skin7-Dehydrocholesterol (an intermediate in the synthesisof cholesterol that accumulates in the skin), undergoesa nonenzymic reaction on exposure to ultraviolet light,yielding previtamin D (Figure 45–3). This undergoes afurther reaction over a period of hours to form the vitaminitself, cholecalciferol, which is absorbed into thebloodstream. In temperate climates, the plasma concentrationof vitamin D is highest at the end of summerand lowest at the end of winter. Beyond about 40 degreesnorth or south in winter, there is very little ultravioletradiation of appropriate wavelength.Vitamin D Is Metabolized to the ActiveMetabolite, Calcitriol, in Liver & KidneyIn the liver, cholecalciferol, which has been synthesizedin the skin or derived from food, is hydroxylated toform the 25-hydroxy derivative calcidiol (Figure 45–4).This is released into the circulation bound to a vitaminD-binding globulin which is the main storage form ofthe vitamin. In the kidney, calcidiol undergoes either1-hydroxylation to yield the active metabolite 1,25-dihydroxyvitaminD (calcitriol) or 24-hydroxylation to yieldan inactive metabolite, 24,25-dihydroxyvitamin D (24-hydroxycalcidiol). Ergocalciferol from fortified foodsundergoes similar hydroxylations to yield ercalcitriol.Vitamin D Metabolism Both Regulates& Is Regulated by Calcium HomeostasisThe main function of vitamin D is in the control of calciumhomeostasis, and in turn vitamin D metabolism is