Tooj
Cov ntsiab lus
Tooj liab yog ib qho tseem ceeb cofactor rau oxidase enzymes catalyze oxidation-txo cov tshuaj tiv thaiv nyob rau hauv ntau yam metabolic txoj kev. Cov tooj liab-dependent enzymes, los yog cuproenzymes, koom nrog, piv txwv li, lub zog (ATP) ntau lawm, hlau metabolism, sib txuas cov ntaub so ntswg, thiab neurotransmission.(Xav paub ntxiv)
Dietary tooj liab insufficiency nyob rau hauv tib neeg tau infrequently piav; Txawm li cas los xij, tooj liab depletion tuaj yeem tshwm sim vim muaj cov kab mob hauv plab hnyuv, kev noj zinc ntxiv, lossis hauv cov kab mob xws li Menkes kab mob. Kev nqus tooj liab hauv plab yog qhov cuam tshuam loj heev hauv Menkes kab mob, ua rau lub cev tsis muaj tooj liab. Cov tsos mob ntawm lub cev tsis tshua muaj tooj liab muaj xws li anemia, pob txha thiab cov ntaub so ntswg txawv txav, thiab kev ua haujlwm tsis zoo ntawm lub paj hlwb.(Xav paub ntxiv)
Kev ntsuas tooj liab hauv tib neeg yog qhov nyuaj, vim tias tsis muaj cov cim biomarkers muaj tseeb rau kev kuaj pom qhov nruab nrab, lossis subclinical, tooj liab tsis txaus. Txoj kev loj hlob ntawm ntau meej thiab rhiab biomarkers ntawm tooj liab khoom noj khoom haus yog li ib qho tseem ceeb rau kev tshawb fawb yav tom ntej.(Xav paub ntxiv)
Kev tsis sib xws ntawm tooj liab hauv tib neeg ua rau muaj kev pheej hmoo ntawm pob txha demineralization thiab osteoporosis, kab mob siab rog, kab mob siab tuag, thiab kab mob plawv thiab neurodegenerative. Hauv qee lub xeev pathological, dysregulation ntawm tooj liab homeostasis yuav tsis yog thawj qhov tshwm sim tab sis tuaj yeem yog qhov thib ob rau qee yam ntawm cov kab mob pathogenesis.(Xav paub ntxiv)
Kev ntsuas kev noj zaub mov kom raug tooj liab yog qhov nyuaj vim tias cov ntsiab lus tooj liab ntawm ntau cov khoom noj tsis tau ruaj khov. Cov nqaij nruab deg, plhaub ntses, txiv ntseej, noob, nplej-bran cereals, thiab cov khoom lag luam tag nrho yog, txawm li cas los xij, tau lees paub tias yog qhov zoo ntawm kev noj haus tooj liab.(Xav paub ntxiv)
Copper toxicity tsis tshua muaj, feem ntau cuam tshuam nrog Wilson tus kab mob, qhov tsis tshua muaj tshwm sim hauv cov metabolism uas ua rau tooj liab overload pib hauv daim siab thiab tom qab ntawd hauv lwm cov ntaub so ntswg, tshwj xeeb hauv lub hlwb. Cov tshuaj lom ntawm tooj liab overload hauv Wilson tus kab mob suav nrog cuam tshuam ntawm lipid metabolism, nrog rau kev puas tsuaj rau mitochondria. Toxic tooj liab txuam kuj tseem pom nyob rau hauv Indian Childhood Cirrhosis thiab Endemic Tyrolean Infantile Cirrhosis (los yog Idiopathic Copper Toxicosis). Tsis muaj cov kab mob caj ces cuam tshuam tau txuas nrog cov kab mob tom kawg no, txawm hais tias muaj kev cuam tshuam ntau ntxiv rau cov tooj liab ntau ntxiv.(Xav paub ntxiv)
Copper (Cu) yog ib qho tseem ceeb ntawm cov kab mob rau tib neeg thiab lwm yam tsiaj. Hauv cov kab ke lom neeg, tooj liab tau hloov pauv ntawm lub khob (Cu1+) thiab cupric (Cu2+) cov ntawv. Lub redox zog ntawm tooj liab underlies nws lub luag haujlwm tseem ceeb hauv oxidation-txo cov tshuaj tiv thaiv thiab hauv kev tshem tawm cov dawb radicals (1). Txawm hais tias Hippocrates tau hais tias tau sau cov tshuaj tooj liab los kho cov kab mob thaum ntxov li 400 BC (2), cov kws tshawb fawb tseem tab tom nthuav tawm cov ntaub ntawv tshiab txog kev ua haujlwm ntawm tooj liab hauv tib neeg lub cev (3).
Muaj nuj nqi
Tooj liab yog qhov tseem ceeb rau kev ua haujlwm ntawm ntau yam tseem ceeb enzymes hu ua cuproenzymes, uas yog qhov tseem ceeb ntawm ntau txoj hauv kev metabolic (4, 5). Physiologic functions ntawm cov tooj liab-dependent enzymes, thiab cov biochemical txoj hauv kev uas lawv ua hauj lwm (6, 7), tau piav qhia hauv qab no.
Kev tsim hluav taws xob
Copper-dependent enzyme cytochromecoxidase (CCO) plays lub luag haujlwm tseem ceeb hauv cellular zog tsim nyob rau hauv mitochondria los ntawm catalyzing txo cov molecular oxygen (O2dej (H2O), yog li tsim hluav taws xob gradient uas yuav tsum tau rau ATP ntau lawm (8). Redox-active tooj liab muaj nyob rau hauv CCO enzyme complex yog xav tau rau cov electron hloov cov tshuaj tiv thaiv uas tseem ceeb rau nws txoj haujlwm.
Kev sib txuas cov ntaub so ntswg
Lwm cuproenzyme, lysyl oxidase (LOX), yuav tsum muaj rau kev sib txuas ntawm collagen thiab elastin fibers, uas yog qhov tseem ceeb rau kev tsim cov ntaub so ntswg uas muaj zog thiab hloov tau. LOX muaj nuj nqi yog qhov tseem ceeb rau kev tsim cov pob txha thiab kev saib xyuas cov ntaub so ntswg hauv lub plawv thiab cov hlab ntsha (2).
Hlau metabolism
Multi-copper oxidases (MCOs) yog tooj liab-dependent ferroxidases uas ua haujlwm hauv hlau homeostasis. MCOs oxidize ferrous hlau (Fe2+) mus rau ferric (Fe3+) daim ntawv, uas tso cai rau kev khi rau transferrin (lub ntsiab hlau cab kuj) nyob rau hauv cov ntshav, yog li cia hlau thauj mus rau qhov chaw ntawm kev siv (xws li, pob txha pob txha). Cov MCOs muaj xws li: (1) ceruloplasmin (CP), uas muaj 60% -95% plasma tooj liab; (2) daim nyias nyias ntawm CP (GPI-CP), qhia hauv hlwb thiab lwm yam ntaub so ntswg; thiab (3) cov membrane-bound ferroxidases hephaestin (HEPH) thiab zyklopen, uas ua haujlwm hauv cov hnyuv thiab placenta, feem (9, 10). CP poob lawm (Cp-/-) cov nas tuaj yeem khaws cov kab mob siab tshaj plaws tab sis muaj cov tooj liab zoo li qub (11, 12). Ib yam li ntawd, cov tib neeg uas muaj aceruloplasminemia, uas tsis muaj kev ua haujlwm CP, tso saib cov hlau ntau dhau hauv daim siab, hlwb, thiab retina tab sis tsis muaj qhov tsis zoo ntawm tooj liab homeostasis (13). Tsis tas li ntawd, kev nqus ntawm cov hlau thiab hlau los ntawm cov chaw cia khoom (piv txwv li, daim siab) yog qhov tsis txaus ntawm tooj liab, thaum CP thiab HEPH kev ua haujlwm raug txo qis, ntxiv dag zog rau MCOs hauv cov hlau metabolism (14).
Central paj hlwb
Ntau cov txheej txheem physiological nyob rau hauv lub hlwb thiab lub paj hlwb, nrog rau neurotransmitter synthesis thiab tsim thiab tu ntawm myelin, nyob ntawm seb catalysis mediated los ntawm cuproenzymes. Dopamine -hydroxylase, piv txwv li, catalyzes hloov dua siab tshiab ntawm dopamine rau neurotransmitter norepinephrine (15). Tsis tas li ntawd, CCO yuav tsum tau siv rau biosynthesis ntawm phospholipids, uas yog cov txheej txheem tseem ceeb ntawm myelin sheath (2).
Melanin biosynthesis
Lub cuproenzyme tyrosinase (TYR) yuav tsum muaj rau biosynthesis ntawm melanin hauv melanocytes, uas yog ib qho tseem ceeb rau cov pigmentation ntawm plaub hau, tawv nqaij, thiab ob lub qhov muag (2). Tsawg TYR kev ua haujlwm feem ntau yuav piav qhia txog achromotrichia pom hauv chav kuaj tooj liab thiab cov tsiaj ua liaj ua teb, thiab cov depigmentation tau sau tseg hauv cov neeg mob hnyav tooj liab-depleted nrog Menkes kab mob.
Antioxidation
Superoxide dismutase (SOD) ua haujlwm ua cov tshuaj tiv thaiv antioxidant los ntawm catalyzing hloov pauv ntawm cov pa oxygen reactive, xws li superoxide anion (O.2-) thiab hydroxyl radical (•OH), rau hydrogen peroxide (H2O2), uas yog tom qab txo dej los ntawm lwm cov kab mob antioxidant (16). Ob hom ntawm SOD muaj tooj liab: tooj liab / zinc SOD (SOD1), uas yog qhia nyob rau hauv feem ntau cov hlwb, nrog rau cov qe ntshav liab; thiab extracellular SOD (EcSOD), uas tau qhia ntau heev hauv lub ntsws thiab pom nyob rau hauv cov ntshav qis (2). Tsis tas li ntawd, raws li tau hais los saum toj no, ceruloplasmin muaj cov tshuaj tiv thaiv kab mob antioxidant hais txog cov hlau metabolism. Kev ua haujlwm ferroxidase ntawm ceruloplasmin tuaj yeem tiv thaiv ferrous hlau (Fe2+) los ntawm kev koom tes hauv cov teeb meem dawb-radical-generating cov tshuaj tiv thaiv ntawm Fenton chemistry (16).
Kev cai ntawm noob caj noob ces
Copper-related gene nthuav qhia txoj hauv kev zoo li tau tswj hwm ntawm qib tom qab kev txhais lus, qee zaum ntawm cov khoom lag luam ntsig txog cov protein uas teb rau cov qib tooj liab intracellular (17). Cytosolic tooj liab kuj tuaj yeem cuam tshuam rau mRNA qhia qib ntawm cov noob tshwj xeeb, nyob rau hauv koob tshuaj (18-20), cuam tshuam txog kev tswj hwm kev hloov pauv. Piv txwv li, intracellular tooj liab tuaj yeem hloov pauv lub xeev redox ntawm cov hlwb thiab yog li ua rau muaj kev ntxhov siab oxidative, uas tuaj yeem ua rau lub teeb liab hloov txoj hauv kev uas ua rau muaj kev nthuav tawm ntawm cov noob encoding proteins koom nrog hauv kev tshem tawm cov pa oxygen reactive hom (21).
Kev sib cuam tshuam ntawm cov khoom noj
Hlau
Khoom noj khoom haus tooj liab txaus yog tsim nyog rau cov metabolism hauv cov hlau thiab cov qe ntshav liab tsim thiab ua haujlwm. Copper depletion ua rau muaj hlau tsis txaus xws li anemia, thiab hlau accumulates hauv daim siab ntawm cov tsiaj tsis muaj tooj liab. Txoj kev loj hlob ntawm anemia thaum lub sij hawm tooj liab tsis muaj peev xwm yuav txuas mus rau qis CP kev ua si, impaired hlau tso tawm los ntawm lub khw muag khoom nyob rau hauv lub siab, thiab txo cov hlau xa mus rau erythroid marrow, yog li ua rau cov hlau txwv erythropoiesis (saib Hlau metabolism) (2). Txawm li cas los xij, qhov no yuav tsis yog tag nrho zaj dab neeg, raws li tsis ntev los no tau hais los ntawm tus kws tshawb fawb tooj liab ntev, Dr. Joseph R. Prohaska (Univ. of Minnesota, Duluth) (22). Copper depletion kuj txo cov kev ua CP hauv tib neeg, ua rau lub siab hlau ntau dhau thiab yog li ua rau muaj kev pheej hmoo rau oxidative puas thiab daim siab cirrhosis (14). Qhov ncauj tooj liab supplementation rov zoo li qub CP qib thiab plasma ferroxidase kev ua haujlwm, thiab kho cov metabolism hauv cov hlau tsis xws hauv cov ntsiab lus tooj liab (23). Ntxiv mus, cov menyuam mos noj mis nrog cov ntsiab lus hlau siab absorbed tooj liab tsawg dua li cov menyuam mos noj cov qauv uas tsis muaj hlau, qhia tias kev noj cov hlau ntau tuaj yeem cuam tshuam nrog kev nqus tooj liab hauv cov menyuam mos (24). Qhov kev soj ntsuam no kuj tau lees paub nyob rau hauv cov nas thiab nas, qhov chaw noj zaub mov muaj hlau ua rau tooj liab depletion, yog li ua rau cov khoom noj khoom haus tooj liab nce ntxiv (25, 26).
Zinc
Kev noj ntau dhau ntawm zinc ntxiv, ntawm koob tshuaj 50 mg / hnub lossis ntau dua rau lub sijhawm ntev, tuaj yeem ua rau tooj liab depletion. Cov txheej txheem tuaj yeem cuam tshuam txog kev sib xyaw ua ke ntawm metallothionein (MT), ib qho intracellular zinc- thiab tooj liab-binding protein. MT muaj kev sib raug zoo rau tooj liab ntau dua zinc, yog li cov qib siab ntawm MT raug ntxias los ntawm zinc ntau dhau tuaj yeem cuam tshuam tooj liab hauv enterocytes yog li txwv nws cov bioavailability. Qhov no postulate, txawm li cas los xij, raug hu mus rau lo lus nug los ntawm cov kev tshawb fawb ua nyob rau hauv MT-tsis muaj nas, nyob rau hauv uas high enteral zinc tseem txo cov tooj liab absorption, qhia tias zinc siab yuav thaiv ib tug tooj liab transporter (27). Piv txwv li, kev siv tooj liab nce siab tsis tau pom tias cuam tshuam rau zinc noj zaub mov zoo (2, 24). Ntxiv mus, zinc supplementation ntawm 10 mg / hnub rau yim lub lis piam rov qab zoo li qub plasma tooj liab / zinc piv hauv 65 cov neeg mob ntawm hemodialysis mus sij hawm ntev uas tau pib pom cov ntshav qis zinc thiab tooj liab siab. Txawm hais tias kev txhim kho zinc thiab tooj liab ntawm cov neeg mob hemodialysis tuaj yeem cuam tshuam cov txiaj ntsig kev kho mob, txawm li cas los xij, yuav tsum tau soj ntsuam (28).
Fructose
Cov pov thawj ntawm kev sib cuam tshuam tooj liab-fructose feem ntau yog los ntawm kev tshawb fawb siv cov tsiaj sim. Kev noj zaub mov ntau fructose ua rau cov neeg tsis muaj tooj liab tsis txaus hauv cov txiv neej nas, tab sis tsis yog nyob rau hauv cov npua uas nws lub plab zom mov yog anatomically thiab ua haujlwm zoo li tib neeg. Tsis tas li ntawd, kev noj zaub mov ntau ntau ntawm fructose (20% ntawm tag nrho cov calories) tsis ua rau tib neeg cov tooj liab depletion, qhia tias kev noj fructose tsis ua rau tooj liab depletion ntawm qib uas cuam tshuam rau cov khoom noj ib txwm muaj (2, 24). Txawm li cas los xij, kev noj fructose siab thiab tsis muaj tooj liab tuaj yeem yog qhov muaj feem cuam tshuam rau kev ua haujlwm tooj liab tsis muaj peev xwm hauv cov neeg mob uas tsis muaj dej cawv fatty siab (29).
Vitamin C
Txawm hais tias cov tshuaj vitamin C tau tsim cov tooj liab tsis txaus hauv guinea npua (30), cov txiaj ntsig ntawm cov vitamin C ntxiv rau cov khoom noj khoom haus tooj liab hauv tib neeg tsis tshua meej. Ob qhov kev tshawb fawb me me hauv kev noj qab haus huv, cov txiv neej hluas tau qhia tias kev ua haujlwm ntawm ceruloplasmin oxidase tuaj yeem cuam tshuam los ntawm cov koob tshuaj vitamin C ntau ntxiv. Hauv ib txoj kev tshawb fawb, vitamin C noj ntawm 1,500 mg / hnub rau ob lub hlis ua rau muaj kev poob qis hauv CP oxidase kev ua haujlwm. (31). Hauv lwm txoj kev tshawb fawb, cov tshuaj ntawm 605 mg / hnub ntawm vitamin C rau peb lub lis piam ua rau txo qis CP oxidase kev ua, txawm hais tias tooj liab nqus tsis poob (32). Tsis yog ob qho ntawm cov kev tshawb fawb no pom muaj vitamin C ntxiv rau qhov tsis zoo rau kev noj zaub mov zoo tooj liab.
Tsis muaj peev xwm
Clinically evident, los yog frank, noj zaub mov tsis txaus tooj liab yog qhov tsis tshua muaj. Ntshav tooj liab thiab CP qib yuav poob mus rau 30% ntawm ib txwm muaj thaum muaj tooj liab tsis txaus. Hypocupremia kuj tau pom nyob rau hauv cov kab mob caj ces ntawm tooj liab metabolism, nrog rau Wilson kab mob (WD) thiab aceruloplasminemia; Txawm li cas los xij, tsis muaj teeb meem dab tsi tau txuas nrog kev noj zaub mov tsis zoo tooj liab. Ib qho ntawm cov tsos mob tshwm sim feem ntau ntawm tooj liab tsis muaj peev xwm yog anemia uas tsis teb rau kev kho hlau tab sis raug kho los ntawm kev siv tooj liab ntxiv. Nws tau pom zoo tias qhov mob ntshav qab zib no tuaj yeem tshwm sim los ntawm kev ua haujlwm tsis zoo ntawm cov hlau vim kev ua haujlwm CP txo qis, tab sis cov tib neeg uas muaj cov kab mob aceruloplasminemia tsis tas yuav tsim muaj ntshav qab zib ntau (33). Ntxiv mus, nyob rau hauv cov npua tsis muaj tooj liab, plab hnyuv hlau nqus tsis zoo, tab sis hlau faib ntawm cov ntaub so ntswg / kabmob yog qhov qub (34-36). Tsawg cov hlau tsis muaj zog los ntawm kev txo qis yog qhov tsis zoo ua rau cov ntshav ntshav no vim tias kev muab cov hlau tso rau hauv cov hlab ntsha tsis kho nws. Lwm txoj hauv kev postulate yog tias tooj liab-deficiency anemia yog tshwm sim los ntawm kev ua tsis taus hemoglobin ntau lawm thiab cov qe ntshav liab proliferation, thiab luv luv erythrocyte lifespan. Cov txheej txheem physiological li no yuav xav tau tooj liab. Tsis muaj tooj liab kuj tuaj yeem ua rau neutropenia, uas tuaj yeem ua rau muaj kev kis kab mob. Copper depletion cov kev tshawb fawb pom tau tias tsis tshua muaj tooj liab yuav cuam tshuam rau erythroid thiab myeloid cell kab mob, txhawb lub luag haujlwm rau tooj liab hauv kev tswj hwm ntawm cov ntshav cell proliferation thiab maturation (37, 38). Kev tshawb fawb ntxiv yog xav tau kom paub meej ntxiv txhawm rau txheeb xyuas cov txheej txheem hauv qab ntawm tooj liab deficiency-induced anemia thiab neutropenia (4, 39). Tsis tas li ntawd, osteoporosis thiab lwm yam txawv txav ntawm kev loj hlob ntawm pob txha tau piav qhia nyob rau hauv cov tooj liab tsis muaj, cov me nyuam mos thiab cov me nyuam mos. Tsis tshua muaj cov yam ntxwv ntawm tooj liab tsis muaj peev xwm muaj xws li kev loj hlob tsis zoo, depigmentation, thiab kev loj hlob ntawm cov kab mob neurological (2, 8).
Biomarkers ntawm tooj liab xwm txheej
Tam sim no, tsis muaj ib qho rhiab thiab tshwj xeeb biomarker los kuaj xyuas qhov tsis txaus tooj liab hauv tib neeg (5, 40-42). Ntshav tooj liab (43) thiab ceruloplasmin concentrations raug txo qis hauv qhov tsis muaj tooj liab loj (3, 6). Txawm li cas los xij, ob qho tib si ntawm cov kev txwv no tseem cuam tshuam los ntawm kev xeeb tub, kev mob, thiab kev kis kab mob (5), yog li txwv tsis pub muaj txiaj ntsig ntawm cov kev ntsuas no los kwv yees lub cev tooj liab. Kev sim ua haujlwm tsis ntev los no tau txheeb xyuas lwm cov biomarkers tooj liab, suav nrog erythrocyte tooj liab Cu / Zn superoxide dismutase (SOD1) thiab tooj liab chaperone rau superoxide dismutase (44-46), tab sis yuav tsum muaj kev sim ntxiv, suav nrog kev kuaj mob hauv tib neeg.
