ΙΙΙ. FAT SOLUBLE VITAMINS

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Corey Briggs
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1 ΙΙΙ FAT SOLUBLE VITAMINS A Generalities 1 Are absorbed in association with lipids -- bile required for absorption 2 Conditions precipitating deficiency state include cholitis, blockage of bile duct, sprue, ingestion of large amounts of mineral oil, etc 3 Vitamins A and D are stored in liver takes time to bring on a deficiency state B Vitamin A 1 Chemistry a Series of compounds are active, eg, retinol (A 1, alcohol), retinal (A 1 aldehyde), and retinoic acid (A 1 acid) 11 CH 2 OH retinol COOH retinoic acid A 2 series also active: R A 2 series Animals -- source of retinyl esters Plants -- source of carotenoids 27

2 b Carotenoids -- "provitamin A" -- source is plants; are converted to retinol in vivo β-carotene is the most active; 15 β-carotene metabolized at the 15 position to yield retinal retinal α-carotene -- ring double bond isomerized; half the activity of β-carotene γ-carotene -- both rings opened - little activity 2 Source -- plants/carotenoids, animals/retinal 3 Transport dietary β-carotene (plants) intestinal mucosa 15,15 dioxygenase, O 2 retinal retinaldehyde oxidase NADH esterases retinol palmitate retinoic acid cell as retinol bound to specific receptor tissues (as retinol bound to retinol binding protein) liver (as retinol palmitate) retinoic acid -- differs from retinol as follows: different binding proteins different cell receptors different T1/2 not stored not found in liver but in skin, eye, ovaries won't replace retinol in relieve of the visual and reproductive abnormalities seen in the vitamin A deficiency state 4 Deficiency state -- Night blindness; xeropthalmia, which may lead to blindness; keratinization of epithelial tissues often accompanied by infections (hence, the name "antiinfective vitamin"), impaired fertility 28

3 5 Function -- Coenzyme form unknown at present and specific biochemical role other than in vision is uncertain a Vision -- component of light sensitive pigment, rhodopsin opsin rhodopsin (opsin + 11-cis-retinal) hv 11 cis retinal all trans retinal + NAD NADH retinal reductase 11 cis retinol retinol (A 1 ) isomerase b Normal differentiation of epithelial tissues Necessary for normal differentiation of epithelial tissues and membrane integrity and function -- retinoic acid plays an important role here c Growth d Necessary for reproduction due to involvement in progesterone and corticosterone biosynthesis e Free radical scavenger (as carotene mainly) and quencher of singlet oxygen We will discuss this later 6 Requirement -- adult DV = 5,000 IU, RDA = 1,000 µg retinol, equivalents (RE), 1 RE = 1 µg retinol or 6 µg β-carotene 7 Source -- fish oils (Vitamin A), fresh vegetables (carotenes), liver 8 Stability -- O 2 labile, as are most fats 9 Use a Deficiency state b Acne -- topically as retinoic acid Systemically as 13-cis retinoic acid (isotretinoin) Accutane Roche Attention: these retinoids are strong teratogens c Cancer -- Vitamin A deficiencies associated with increased sensitivity to carcinogens and increased tumor incidence; doses of A required to have antitumor effects or to prevent tumors are too high for safe use, therefore, less toxic retinoids are being evaluated Those most promising retinoids are not transported on retinal binding protein and are not stored There is an association of low carotene intake and increased risk of lung cancer in smokers However, supplementation of beta carotene to smokers gave an increased risk of lung cancer! d Psoriasis -- Etretinate Tegison Roche 29

4 e Retinol being evaluated in some Third World countries to decrease mortality in children due to measles and other infectious diseases One study showed that severe measles in the USA was associated with low retinol levels f Fat soluble free radical scavenger 10 Toxicity a Hypercarotenosis -- eat too many carrots -- turn yellow, but no harm done b Hypervitaminosis A -- characterized by hydrocephalus, vomiting, hypercalcemia, fatigue, malaise, joint pain, headaches, rough skin, swellings on the extremities, papilledema caused by increased production of spinal fluid (symptoms of brain tumor), hepatotoxicity Can be precipitated by chronic ingestion of 50,000 IU day or acute ingestion of 300,000 IU/dose c Teratogenic? - recent evidence says yes in doses > 10,000 IU/d Note: Watch out for polar bear liver -- has 20,000 to 30,000 IU/g Systemic retinoids may cause photosensitivity Systemic retinoids are teratogenic Is vitamin A in high doses teratogenic?? 30

5 C Vitamin D 1 Structures D-1 through D-4 1 H 2 UV light HO 7-dehydrocholesterol HO vitamin D 1 - mixture vitamin D 2 - ergocalciferol vitamin D 4 - dihydroergocalciferol 23 UV light CH 2 etc ergosterol vitamin D 2 (ergocalciferol) HO 2 1 vitamin D 3 (cholecalciferol) 2 Deficiency state -- rickets, ostemalacia 3 Function -- Vitamin D is necessary for absorption of Ca through the intestinal mucosa, and is necessary for functioning a "Ca pump" Ca is necessary for active absorption of phosphate so that Vitamin D indirectly affects phosphate levels 1,25-dihydroxy D 3 acts as a hormone in regulating synthesis of calcium binding protein at gene expression level calcium in gut (dietary) vit D calcitonin plasma calcium calcitonin PTH bone calcium 31

6 4 Metabolites -- diet cholecalciferol skin 7-dehydrocholesterol blood plasma (Cholecalciferol) liver P450 (25-hydroxycholecalciferol) blood plasma (circulating 25-hydroxycholecalciferol) bound to protein mitochondrial kidney enzyme High Ca ++ 24,25-DHCC (inactive) 4-13 times more active than D 3 (1, 25-dihydroxycholecalciferol) tissue Rocaltrol Roche (Calcitriol) 25 µg and 5 µg (Bone, intestinal mucosa, skeletal muscle) 5 Toxicity -- avoid high doses, especially in infants, 400 units/day = potentially toxic for infant, 150,000 units/day = potentially toxic for adult, calcification of soft tissues (lung, kidney) 6 Requirements -- DV = 400 IU; RDA = 10 µg, cholecalciferol 7 Source -- fish liver, fish products, sunshine, eggs, liver, milk (fortified) 8 Use -- deficiency state and in hypoparathyroidism to keep serum levels adequate; used in osteomalacia and osteoporosis Use hydroxy derivatives in renal failure There is now strong evidence that vitamin D supplements and calcium help prevent fractures in postmenopausal women Calcitriol is more potent Calcitriol (Rocaltrol Roche) -- 1,25-dihydroxy D 3 -- the "active" metabolite Dihydrotachysterol -- an analog that does not have to be activated by the kidney Calcifediol (Calderol Upjohn) hydroxy D 3, less potent but still effective There is an inverse association of D & Ca intake and risk for colon cancer Also milk consumption 32

7 D Vitamin E 1 Structure CH 3 CH 8 3 O * CH 3 CH 3 CH 3 CH 3 7 (CH 2 ) 3 CH (CH 2 ) 3 CH (CH 2 ) 3 CH CH 6 3 HO * * 5 CH 3 There are 8 possible stereoisomers "Natural" vitamin E is RRR-α-tocopherol RBC levels of RRR are higher than with an equal dose of the racemate 2 Activity d-α-tocopherol 1 mg = 15 IU dl-α-tocopherol 1 mg = 11 IU dl-α-tocopherol acetate 1 mg = 10 IU Other tocopherols are active: β = 7-demethyl 1 mg = 01 IU α = 5-demethyl 1 mg = 01 IU δ = 5,7-demethyl 1 mg = 01 IU (present in large amounts of corn) dl-α-tocopherol acetate 1 mg = 10 IU 1 tocopherol equivalent (1 TE) = 1 mg d-α-tocopherol 20 mg TE 30 IU= DV 3 Stability Much is lost during processing and cooking White, bleached flour has almost all E destroyed E O 2 O O HO R inactive Iron catalyzes the oxidation α tocopherylquinone 4 Properties -- Good fat soluble antioxidant, good free radical scavenger Has mild effect in decreasing platelet aggregation due to an effect on decreasing the activity of cyclooxygenase (therefore decreased conversion of arachadonic acid to thromboxane) 5 Distribution -- Almost ubiquitous; rich sources are seed germ oils, green vegetables, whole grain cereals; margarine supplies much of our intake in the US 33

8 6 Deficiency state Animal Species Rat (male) Rat (female) Rabbit Dog and Guinea Pig Primate Syndrome sterility, liver necrosis fetal resorption, liver muscular dystrophy, myocardial degeneration Myocardial degeneration Macrocytic anemia, muscular dystrophy Man A dietary deficiency of E is rare A deficiency state was seen in some premature infants (stores of E are low at birth due to poor placental transport where edema and hemolytic anemia has been observed when the infants were fed a formula low in E and high in polyunsaturated fatty acid) In diseases resulting in malabsorption of fats, a neurological impairment observed has responded to vitamin E 7 Requirement -- DV = 30 IU 8 Biological function of E -- Acts as a general fat soluble biological antioxidant to prevent free radical oxidation of lipids and hence essential membrane destruction More on this later R + O 2 RO 2 RO 2 + RH ROOH + R etc readily polymerizes Evidence for this : In vitro can show increased peroxide formation in tissues taken from E deficient animals; effect varies with polyunsaturated fatty acid (PUFA) intake -- the higher the PUFA in diet the more E is required to prevent the deficiency state; some other antioxidants can be substituted for E to prevent some (not all) of the deficiency symptoms in animals; various age pigments (composed of perioxidized lipids) appear in certain tissues in E deficient animals and humans; BHT and other antioxidants have prolonged the life span of rats 9 Uses -- The claims for benefit of vitamin E are numerous and include increased virility, increased athletic performance, and a cure for diabetes, heart disease and aging There is no evidence to evaluate these claims with the following exceptions: a Intermittent claudication -- Long-term treatment with 400 IU/day; vitamin E has been reported to be of benefit in two older clinical studies b Angina -- No significant benefit found in double blind, crossover study Ref: Am Heart J, 93:444 (1977) c Athletic performance -- No benefit in competitive swimmers Ref: Br J Nut, 26:265 (1971), J Sports Med, 16:215 (1976) d Nocturnal leg cramps -- Evidence is suggestive of benefit, but careful evaluation has yet to be done 34

9 e Increased sexual performance and function -- Sorry, no help here! f Retrolental fibroplasia and Brochopulmonary dyspasia Eye and lung damage in premature infants on oxygen; as an antioxidant, E seems to offer some protection, but deaths have occurred These deaths occurred in Wash State and were associated with IV admin of tocopherol This form is no longer available and MVI Pediatric (Astra) is used as a source of IV Vitamin E for premature infants g PMS -- one controlled study showed benefit Controversial h Various uses as an antioxidant and free radical scavenger Will discuss later Daily use of Vitamin E supplements in doses of > 100 IU has been associated with a decreased risk for coronary heart disease in both men and women (New Eng J Med 328:1450, 1993 and 328:1444, 1993) Results are mixed using E in patients with existing heart disease i Topical Use j Alzheimers Disease -- high doses (2000 IU/d) showed some benefit k Cancer use gave decreased risk for prostate cancer in smokers 10 Toxicity --Tocopherols are generally considered non-toxic Various rare diverse adverse effects have been reported Exacerbated bleeding when given together with coumarin anticoagulants is the most significant drug interaction involving Vitamin E E Vitamin K -- Group of napthoquinones having antihemorrhagic activity 1 Chemical Natural K 1 -- Phytonadione USP, from plants, n = 4 O CH 3 CH 3 (CH 2 CH C CH 2 ) n H O K 2 -- Menaquinones, from bacteria, n = Function -- Necessary for carboxylation of γ glutamyl residues on precursor proteins activation blood coagulation 3 Deficiency -- Deficiency state can come on fast because K is not stored Long term antibiotic therapy may increase risk of deficiency because ~ 50% comes from intestinal bacteria 35

10 4 Use -- Water soluble derivatives used for IV and where absorption is impaired For an anticoagulant overdose, use K1 K1 is used routinely at birth IM to prevent neonatal hemorrhage 5 Source -- Spinach, cabbage, tomatoes, other green vegetables 6 Dose -- No RDA ca 5-25 mg used 7 Toxicity IV OXIDATIVE STRESS AND PROTECTIVE MECHANISMS INVOLVING VITAMINS Reactive oxygen species that result in tissue damage (drugs, pesticides, pollutants can cause tissue damage via oxidative metabolism) Importance - inflammation, carcinogenesis, hemolysis, athroscherosis, arthritis, aging, drug adverse effects Reactive O 2 species causing damage: - Complete reduction of O 2 O 2 + 4H + + 4e - 2H 2 O but this goes in 1 electron steps e - _ e - O 2 O 2 - Reactive species O 2-2 H + H 2 O 2 e - O -2 + e - 4H + O H 2 O Cu +++ _ O 2 HOOH Cu++ _ + Fe ++ OH + OH + O 2 hydroxy hydroxy anion radical Fe +++ _ O 2 + H + HO 2 perhydroxy radical - Origin of e - - oxidation of hydroquinones, flavins, thiols, drugs, mitochondrial respiration, microsomal reactions, UV light radiation, etc 36

11 Targets - DNA, thiols, enzymes, membranes, collagen, lipids, eg, unsaturated lipid COOH H H OH H O 2 + H 2 O etc O 2 R + OOH RH O O peroxy radical OR + OH lipid peroxide O 2 Fe ++ Fe +++ polymers O etc + OH - + O 2 Protective Mechanisms 1 Glutathione pathway 2ROH + O 2 Glutathione peroxidase (Selenium) 2GSH GSSG Glutathione reductase (FAD) FAD NADP NADPH Glucose 6 phosphate dehydrogenase Glucose 6 phosphate 6 phosphogluconic acid 37

12 2 Superoxide dismutase: 2 O 2 _ H + H 2 O 2 + O 2 3 Catalase: 2 H 2 O 2 2 H 2 O + O 2 4 Vitamins A, β-carotene, C, and E and selenium R _ OO (β-carotene) Vitamin E ascorbic acid NADH R _ OOH Vitamin E ascorbic NAD acid Issues: Should supplements of antioxidant vitamins be routinely recommended? Is there evidence that antioxidant use has long term benefit? Are there adverse consequences of taking antioxidant supplements? What doses should be used if use is deemed safe and worthwhile? V MULTIVITAMINS A Need? Do we need to supplement diets with multivitamins? FDA says no; others say maybe in certain circumstances Cases where multivitamin supplements may be worthwhile: Inadequate intake -- alcoholics, poor, elderly, dieters, poor diet Poor absorption -- elderly, GI disorders, cystic fibrosis, diarrhea Increased needs -- pregnancy, lactation, infants, smokers, injury, trauma, surgery, infection Iatrogenic Vitamin Deficiencies -- oral contraceptives, long term antibiotic use, isoniazid, cholestyramine B Available multivitamin preparations -- product selection guidelines 38

D. Vitamin K -- Group of naphthoquinones having antihemorrhagic activity.

D. Vitamin K -- Group of naphthoquinones having antihemorrhagic activity. 1. Structures VITAMIN K1; Phytonadione; 2-Methyl-3-phytyl-1,4-naphthoquinone VITAMIN K2; Menaquinone-6 and 7; N=6,7 n 2. Function