Recap 6 (nutri) Flashcards
2 phases of xenobiotics products metabolism
- Chemical undergo hydrolysis, oxidation or reduction
- catalyst = CP450 (+++ hepatocytes in ER) -> detoxify xenobiotics or convert into active compounds -> produce ROS
- CYP inducer = chemicals, drugs, smoking, alcohol, hormones = bind to Sp receptors (PPAR, CAR, PXR) -> heterodimerize with retinoic X receptor (RXR) -> active promoter of CYP
- CYP inhibitors = fasting, starvation - Transforming into water-soluble compounds : glucuronidation, sulfation, methylation, conjugation with glutathione
Effects of O3 (ozone air polluant)
Produced by interaction of UV and O2 = ozone layer
Ground level ozone = formed by rx of nitrogen oxides and volatile organic compounds -> ROS injure respi epith cell and type 1 alveolar cells
Effects of CO
Systemic asphyxiant
Source =incomplete oxidation of hydrocarbons
Short lived in atmosphere because rapidly oxidized to CO2
SNC depression
++ischemic changes in basal ganglia and lenticular nuclei
Cherry-red color of skin
If prolonged = edema brain, H+, neuronal change not Sp = systemic hypoxia
Effects of radon
Radioactive gas derived from uranium in soils and homes
Lung cancer
Morphology of lead toxicity
Bind sulfhydryl (high affinity) groups = interfere with calcium metabolism -> hematopoietic, skeletal, neuro, GI, renal toxicity
Interferes in 2 enzymes in heme synthesis = delta aminolerulinic acid dehydratase and ferrochelatase = iron incorporation in heme in impaired
Inhibe Na et K dependent ATPase = RBC fragle = hemolysis
1. Blood and bone marrow =
inhibe ferrochelatase -> ring sideroblast (punctuate basophilic stipping), red cell precursors with iron laden mitochondria
microcytic hypochromic anemia with mild hemolysis
2. Children irreversible, adult reversible
3. DX = elevated blood lead and GR free protoporphyrin or zinc protoporphyrin
4. 80-85% absorb in developing teath and bone, 5-10% blood, rest = soft tissue
Mercury, effects, soruces, mechanism
Binds sulfhydryl groups in certain proteins with high affinity = CNS, kidney
Source = mercury vapor from dental amalgams, contaminated fish
Effects = lipid solubility facilitate accumulation in brain, gut (ulcers, bloody d+), renal failure
- IC GSH act as sulfhydryl donor = main protective mechanism against mercury
Arsenic toxicity
Interferes with mitochondrial oxidate phosphorylation
—> sensorimotor neuropathy, hyperT, skin changes, risk cancer
++ TGI, nervous system, skin, heart
Calcium toxicity
Requires uptake into cells by tramsporters = ZIP8
-> lungs and kidneys
Benzene, 1,3-butadiene toxicity
Increase risk of leukemia
Disrupt progenitor cell differentiation
Benzene is oxidized to an epoxide by CYP2E
Bisphenol (BPA) toxicity
Endocrine disruptor, heart disease
Carcinogens in lung cancers
Polycyclic hydrocarbon and nitrosamines
Metabolism of alcohol
Absorb in stomach/small intestines -> distribution -> metabolized to acetaldehyde in liver by 3 enzymes = deshydrogenase (cytosol), CP450, enzymes (RE) and catalase -> convertion to acetaldehyde dehydrogenase to acetate = used in mitochondria respiration chain or lipid synthesis
Effects of alcohol
- alcohol oxidation causes reduction of NAD (need for fatty acid oxidation of lactate in pyruvate) -> accumule fat in liver
- ROS generation by metabolism by CYPE1
- release LPS of G- in flora -> production TNF by Kupffer -> hepatic injury
Acetaminophen metabolism
95% detox by phase II enzymes liver
5% metabolized by CYP2E to NAPQI (centrolobular necrosis)
NAPQI covalently bind hepatic proteins = damage to cellular membrane and mitochondria dysfunction
Lungs injury :
1. Water soluble gas
2. Lipid soluble gas
- Water = chlorine, sulfur oxides, ammonia = react with water to form acids/alkalis -> inflamm and swelling -> partial/complete obstruction
- Lipid = nitrous oxide = reach deeper airways producing pneumonitis
Mechanism of heat stroke
Sustained contraction of skeletal muscles, muscle necrosis by nitrosylation of RYR1 in the sarcoplasmic reticulum of skeletal muscle -> allows calcium to leak into cytoplasm -> stimule muscle contraction and heat production
etiology of malignant hyperthermia
Mutations in gene like RYR1 that control calcium levels
Exposure to certain anesthetic triggers rapid rise in calcium -> muscle rigidity + increase heat production
Ionizing radiation on lymphoid systems
High/large exposure = severe lymphopenia within hours, shrink lymph nodes and spleen (radiation kills lympho directly)
Brief rise in neutrophils followed by neutropenia within several days
Granulocytes return to normal within 2-3 months
Very high dose = kill hematopoietic stem cells = permanent aplasia
Marasmus (severe lack of calory) mechanism
Low production of leptin -> stimule hypothalamic-pituitary-adrenal axis to produce cortisol that contribute to lipolysis
Marginal depletion of visceral proteins and somatic proteins
Anorexia and bullumia pathognomonic change
Increase fat in bone marrow with mucinous matrix = pathognomonic
What vitamines can be endogenously synthesized?
D = from precursors steroids
K, biotin = intestinal, microflora
Niacin = from tryptophan (amino acid)
Vitamine A function, metabolism
Maintain normal vision = with 4 forms of vit A(rhodopsin, iodopsin)
Regulation cell growth/differenciation = activation of retinoic acid receptor (RAR)= release of corepressors and formation of heterodimers with another retinoid receptor (RXR)
-> all-trans retinoic acid highest affinity for RAR
Regulation of lipid metabolism = RXR activated by 9-cis retinoic acid
- B carotene converted to vitA
- absorption requires bile, pancreatic enzymes, antioxidant activity in food
Vit A deficiency and toxicity
DEFICIENCY = vision loss, eptih metaplasia, dry eye, loss mucociliary epith respi, desquame keratin debris in urinary tract (stone), hyperplasia/keratin of epidermis (dermatosis), immune deficiency
TOXICITY
Aigue - headache, dizzy, v+, stupor, blurred vision
Chronic - retinoic acid stimulate osteoclast = bone resorption. Synthetic retinoids = teratogenic effects
VitD sources
Endogenous synthesis from 7-dehydrocholesterol in a photochemical rx -> cholecalciferol (vitD3)
Diet = ergosterol (plants, grain, fish)
VitD metabolism steps
- Photochemical synthesis of vitD from 7-dehycrocholesterol in the skin and absorb vitD from food in guts
- Binding of vitD to plasma a1-globulin (DBP) and transport to liver
- Conversion of vitD into 25-hydroxycholecalciferol (25-OH-D) in the liver by CYP27A1
- Conversion of 25-OH-D into 1,25 dihydroxyvitamine D in the kidney by enzyme a1-hydroxylase
1,25 dihydroD binds nuclear vitamine D-R -> associates with RXR
Also binds membrane-associated vitD-R (mVDR) activate protein kinase C = open calcium channels
Immunomodulatory, antiproliferative effects
VitD regulation in kidneys
HYPOCALCEMIA = stimule secretion of PTH -> hausse conversion of 25-OH-D to 1,25 dihydroxyvitamine D by upregulating 1a-hydroxylase
HYPOPHOSPHATEMIA = upregulate 1a-hydroxylase
Effects of vitD on calcium and P
- stimule intestinal Ca absorption (1,25dihydroD increase absorption by increase expression of TRPV6
- stimule calcium reabsorption in kidney (expression of TRPV5 = Ca influx in distal tubule)
TRPV5 also regulated by PTH - 1,25dihydro and PTH enhance expression of RANKL (R-activator or NFkB) on osteoclasts -> RANKL binds RANK on preosteoclasts induce maturation -> secretion of hypochloric acid and active proteases (cathepsin K) -> release Ca and P
- mineralisation of bones = stimule osteoblasts to synthesize osteocalcin (calcium-binding protein involved in Ca deposition)
VitD deficiency
Less vitD = hypocalcemia = elevated PTH :
- active renal 1a-hydroxylase = increase active vitD and calcium absorption
- increase resorption of calcium from bone
- decrease renal calcium excretion, increase renal phosphate excretion (normal calcium restored but hypophospho can persist = impaired bone mineralisation)
Non skeletal effect of vitD
Synthesis of 1,25dihydroD by CYP27B in macrophages can be stimulated by TLR during infections
Functions of vitC
Activates prolyl and lysyl hydroxylase from inactive precursors = hydroxylation of procollagen
Antioxidant
Modulate immune response
Mechanism of obesity
- Nutrient intake -> POMC cleaved from POMC/CART neurons -> a-melanocyte-stimulating hormone (MSH) -> active MC3/4R-R in 2nd order neurons -> reduce food intake and increase energy expenditure by producing BDNF, TSH and CRH
- Fasting active NPY/AgRP neurons to release NPY = active Y1 et Y5-R in 2nd order neurons = increase food intake by producing MCH and orexin + reduce energy expenditure by downregulating sympathetic output
- NYP/AgRP neurons directly inhibit POMC/CART neurons
Leptin (secreted by fat cells) pathology in obesity
Mutation in leptin gene or R = massive obesity
Mutation in melanocortin-R 4 gene (MC4R) more common
Anorexigenic response of leptin blunted in obesity = leptin resistance
Insulin exerts = anorexigenic response
Pathogenesis of thermogenesis
Catabolic effect, controlled by hypothalamic signals that increase the release of norepinephrine from sympathetic nerve endings in adipose tissue
Functions of adiponectin
- stimulate fatty acid oxidation in skeletal muscle = reduce levels
- decrease glucose production in liver
- increase insulin sensitivity
- antiinflamm, antiatherogenic, antiprolif and cardioprotective
R = AdipoR1 et R2
Binding of adiponectin = active cAMP-dependent kinase (prot kinase A) -> phospho et inactive acetyl coenzyme A carboxylase (needed for fatty acid synthesis)
Production of cytokines by white adipose tissue
TNF, IL1, IL6, IL18
In obese = chronic proinflamm state with high levels of C-reactive protein (CRP)
What does insulin resistance and hyperinsulinemia lead to?
Leads to retention of sodium, expansion of blood volume, prod of excess norepinephrine, smooth muscle proliferation = hallmarks of hypertension
Possible mechanisms in cancer
- Elevated insulin level (rise insulin-like growth factor 1 = mitogen, IGFR-1 activates RAS and PI3K/AKT)
- effects on steroids hormones = cell growth in breast, uterus, other
- adiponectin reduced and it normally suppress cell proliferation and promotes apoptosis by promoting p53 and p21
- proinflammatory state
What does mutation in codon 249 of TP53 gene indicate?
Signature of aflatoxine exposition
