Unit 10 Vitamin A PDF

Unit 10: Adverse Effects of Vitamins → The Example of Vitamin A  Tolerable Upper Intake Level (UL) *not intended to be a recommended intake level Highest level of continuing daily nutrient intake that is likely to pose no risk of adverse effects in almo...

Unit 10: Adverse Effects of Vitamins → The Example of Vitamin A  Tolerable Upper Intake Level (UL) *not intended to be a recommended intake level Highest level of continuing daily nutrient intake that is likely to pose no risk of adverse effects in almost all individuals Risk of adverse effects increases with nutrient intakes ABOVE the UL UL based on TOTAL INTAKE from foods + fortified foods + supplements Risk of Adverse Effects Risk of Inadequacy TI = UL ÷ RDA Dangerous Intakes TI = Therapeutic Index Observed Level of Intake (low to high)  DRI Table: Vitamin A μg/day (RAE) → Retinol Activity Equivalents EAR RDA/AI* UL Infants 0-6 mo ND 400* 600 7-12 mo ND 500* 600 Children 1-3 y 210 300 600 4-8 y 275 400 900 Adult Males 9-13 y 445 600 1700 14-18 y 630 900 2800 19-30 y & 31-50 y 625 900 3000 51-70 y & >70 y 625 900 3000 Adult Females 9-13 y 420 600 1700 14-18 y 485 700 2800 19-30 y & 31-50 y 500 700 3000 51-70 y & >70 y 500 700 3000 Pregnancy < 18 y 530 750 2800 19-30 & 31-50y 550 770 3000 Lactation < 18 y 885 1200 2800 DRI Vitamin A, 2001; http://nap.edu/10026 19-30 y & 31-50y 900 1300 3000 Vitamin A Compare the TI between TI = 3000 μg ÷ 900 μg = 3.33 (adult males) TI = 3000 μg ÷ 700 μg = 4.3 (adult females) Vitamins Vitamin E (same UL and RDA for adult males and females) TI = 1000 mg ÷ 15 mg = 66.7 The TI, the margin of safety between the RDA and UL intakes is NARROW for Vitamin A and WIDE for Vitamin E. Easy to experience adverse effects with high vitamin A intakes versus other nutrients.  Dietary Sources of Vitamin A Consider your vitamin A intake from COMBINED dietary and supplement/multivitamin sources RDA for Females RDA for Males 700 g RAE UL 900 g RAE Beef liver, pan fried – 3 ounces Pumpkin, canned – 1 cup Carrots, cooked – 1 cup High in Carotenoids Sweet potato, canned – 1 cup Dietary Oatmeal, instant, apples and cinnamon – 1 packet Sources Raisin bran cereal – 1 cup Cheese, ricotta, whole milk – ½ cup Broccoli, cooked – 1 cup Asparagus, fresh – 10 spears 0 400 800 1200 1600 2000 3000 4000 5000 6000 7000 Vitamin A (g) or RAE Figure 10.17. Science of Nutrition; 2017 Data from USDA National Nutrient Database for Reference Standards RAE = Retinol Activity Equivalents Adverse Effects of HIGH Vitamin A Intakes (above the UL) EAR RDA UL Risk of Adverse Effects Risk of Inadequacy 1.0 ↓ bone mineral density, 1.0 ↑ risk fracture Progressive Liver toxicity Skin disorders 0.5 Alopecia 0.5 Nausea Vomiting Teratogensis = birth defects 0.0 0.0 500-625 700-900 3000 12000 15000 30000+ Vitamin A Intake (g/d)  Birth Defect Data Used to Derive the UL for Vitamin A Study Design Subjects Daily Vitamin A Dose Result (μg/day) Dudas, 1992 Cohort 2,713 1,800 supplement vs. placebo No CNC defects observed Rothman, Cohort study 22,748 pregnant ≤ 1,500 to > 4,500 Intakes > 3,000 μg/d, 1995 women increased risk of CNC defects Mills, 1997 Case control 89 cases < 1,500 to > 3,000 CNC defects at ≥4500μg/d 573 controls Khoury , 1996 Case control 1,623 cases < 2,400 No increased risks of CNC 3,029 controls defects Shaw, 1996 Case control 925 cases ≥ 3,000 Increased risk of CNC defects 871 controls ≥3,000 μg/d Czeizel, 1998 Case control 20,830 cases Range: 150–30,000 μg/day Birth defects increase with 35,727 controls intakes >3000 μg/d Martinez- Case control 11,293 cases < 12,000 Increased teratogenicity Frias, 1990 11,193 controls ≥ 12,000 ≥ 12,000 Teratogenicity → criteria used for females of reproductive age (UL = 3000μg/day) Birth defects derived from cranial neural crest (CNC) cells Craniofacial malformations (cleft palate and cleft lip) DRI Vitamin A, 2001; http://nap.edu/10026  Liver Abnormality Data Used to Derive the UL for Vitamin A Case Reports Subject Dose (μg/d) Duration (y) Outcome Oren 1992 Woman, 56 y 1,515 10 Severe fibrosis in restricted regions Hatoff 1982 Man, 62 y 7,600 6 Severe hepatotoxicity Kowalski 1994 Woman, 45 y 7,600 6 Severe hepatotoxicity Eaton 1978 Woman, 51 y 8,300–10,600 30 Cirrhosis; marked fibrosis Weber 1982 Man, 62 y 12,000 6 Liver fibrosis Minuk 1988 Man, 62 y 14,000 10 Altered liver function Zafrani 1984 Man, 36 y 15,000 12 Liver fibrosis; stellate cell hypertrophy ; Hepatic Woman, 25 y 26,000 8 lesions Farrell 1977 Woman, 57 y 30,000 4 Altered liver function; stellate cell hypertrophy Geubel 1991 41 cases, Mean, 29,000 Mean, 4.6 - Fibrosis (n = 5) 9–76 y - Stellate cell hypertrophy (n = 9) - Fibrosis with inflammation (n = 10) - Cirrhosis (n = 9) - Death (n = 6) Liver Abnormalities → criteria used for males, senior females, infants and children Adults UL = 3000 μg/day; children UL 600-900 μg/day DRI Vitamin A, 2001; http://nap.edu/10026  Adverse Effects: Hypervitaminosis A Acute vitamin A toxicity from ingesting fish n=11 (age 15-45 yr) liver curry. Single intake of ~40 000 μg vitamin A British Medical Journal (1983) 287:897. Acute Toxicity Symptoms (5-8 hr post-meal) [No authors listed] - Nausea, vomiting - Blurred vision - Superficial peeling of skin (face, neck) - Symptoms lasted ~4 days 4 months 10 000 μg – 45 000 μg/day (supplements or from liver sources) Chronic Toxicity Symptoms: - Vomiting, nausea - Skin rash/alopecia 10 years - Enlarged liver - Liver fibrosis and lipid accumulation in stellate cells - Cirrhosis 10 years  Hypervitaminosis A in Dogs Consider ALL dietary sources of vitamin A…dog food (usually balanced and meets required intake levels) PLUS treats! → Dehydrated liver (storage site of vitamin A) Acute Signs: Vomiting, drowsiness, irritability, and peeling skin Chronic Signs: Poor hair coat, rough or dry skin, weakness, weight loss, constipation, excessive bone development, and painful or limited movement Other Signs: Reduced appetite, lethargy, muscle tremor, inflexibility in the joints, bone pain or fractures, yellowing of the skin (jaundice), excessive thirst and urination, irritation of the eyes and eyelids, and dehydration Vitamin A Poisoning in Dogs | VCA Canada Animal Hospitals  Carotenoids (Pro-Vitamin A) → β-carotene Red, orange and yellow lipid-soluble pigments found in a variety of plants No DRI Recommended: 5+ servings of fruits/vegetables per day = 3-6 mg β-carotene Absorption ranges from 20-50%, cooked/heat-processed forms are more bioavailable versus raw Supplements more bioavailable versus food sources Figure 10.13. Science of Nutrition; 2017 Data from USDA National Nutrient Database for Reference Standards  β-carotene (Pro-vitamin A) Some carotenoids can be converted to vitamin A: – β-carotene → 12 μg = 1 μg retinol (1 RAE) – α-carotene → 24 μg = 1 μg retinol (1 RAE) – β-cryptoxanthin → 24 μg = 1 μg retinol (1 RAE) Synthesis of Vitamin A (all-trans retinal) is by 2 enzymatic cleavage pathways – Central cleavage →15, 15’ dioxygenase produces two molecules of retinal – Non-central cleavage → 9’ 10’ dioxygenase produces β-apo-10’-carotenal and β-ionone – Other enzymes involved in non-central cleavage still unidentified produce various β-apocarotenoids (specifically β-apocarotenals and β- apocarotenones) β-carotene  Identifying cellular and molecular mechanisms of actions of β-apocarotenals and β-apocarotenones ? is an active area of research 15, 15’ dioxygenase 9, 10’ dioxygenase β-apocarotenals x2 ? Retinal (aldehyde form) ? Retinal oxidase x2 Retinol (alcohol form) β-apocarotenones  β-Apocarotenals and β-Apocarotenones: Relationship to Xenobiotic Metabolism β-apocarotenoids are ligands for many transcription factors β-apo-14′-carotenal functions as a transcriptional repressor of the RXR, PPARα, PPARγ, LXRα, and LXRβ β-apo-13-carotenone functions as a transcriptional repressor of the RXR and inhibits expression of CYP26A1 Modest inhibition of any nuclear receptor (listed above) is observed with other examples of β-apocarotenoids ** RXR will heterodimerize with many nuclear receptors → broader implications of inhibiting transcriptional function of various transcription factors/nuclear receptors Connecting Perspectives Already Discussed in Our Course: – High levels of Retinol will decrease CYP expression – β-carotene will increase expression of CYP1A1 and CYP1A2  β-carotene Circulates in VLDL/LDL particles in blood Stored in subcutaneous adipose tissue → high intakes (~20-30mg/day) can lead to the development of hypercarotenemia, orange/yellowing of the skin Functions (evidence from in vitro and animal studies) – Anti-oxidant → e.g. prevent oxidation of LDL cholesterol (α-atherosclerotic effect) – Inhibits cell proliferation → anti-cancer effects Observational studies: ↑ carotenoid intakes associated with ↓ risk of cancer (multiple types) (Ziegler et al., 1996) – Lower risk of lung cancer associated with higher blood levels of β-carotene Study Population Plasma [β-carotene ] Nomura, 1985 Japanese men 0.29 mg/L Menkes, 1986 U.S. men & women 0.29 mg/L Connett , 1989 MRFIT cohort, men 0.12 mg/L “The Research Pyramid” & The Anti-Cancer Effects of β-Carotene In vitro Cell Culture Studies Question: What is the effect of β-carotene supplementation on lung cancer in a randomized, double-blind, placebo controlled human clinical trial? 2 clinical trials (independent from each other but conducted at the same time (USA & Finland) addressing this question using the gold standard study design….what happened?  Adverse Effects of β-Carotene CARET: The Beta-Carotene & Retinol ATBC: α-Tocopherol, β-Carotene Efficacy Trial Cancer Prevention Study 30 mg β-carotene + 7500μg 20 mg β-carotene ± 50 mg α- retinol/day vs placebo tocopherol/day vs placebo n=18,314 males/females, avg. age 57 y n=29, 133 males, avg. age 59 y Compliance assessed by serum Compliance assessed by serum [β-carotene] [β-carotene] – Treatment = 2.1 mg/L – Treatment = 3.0 mg/L Placebo = 0.16 mg/L Placebo = 0.17 mg/L Randomized, double-blind, placebo controlled primary intervention trials High risk population: heavy smokers (30+ yr) & asbestos exposed Primary Endpoint: incidence of lung cancer Baseline characteristics were well matched (treatment vs placebo) Omenn et al., N Engl J Med, 1996; 334:1150 ATBC Study Group, N Engl J Med, 1994;330:1029  Adverse Effects of β-Carotene CARET Study ATBC Study β-Carotene group vs placebo: β-Carotene group vs placebo: 28% ↑ risk of lung cancer 18% ↑ risk of lung cancer (RR= 1.28; 95%CI: 1.04-1.57, P=0.02) (RR= 1.18; 95%CI: 1.03-1.36, P