MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Transportér OATP1B1 - gen slc01B1

SLCO1B1 gene synonyma

  • protein called organic anion transporting polypeptide 1B1
  • OATP1B1, OATP-C, OATP2, LST-1, or SLC21A6
  • Sodium-independent organic anion-transporting polypeptide 2
  • Solute carrier family 21 (organic anion transporter), member 6
  • Solute carrier family 21 member 6
  • Solute carrier organic anion transporter family, member 1B1

Význam a funkce

  • Found in liver cells
      • Liver-specific organic anion uptake transporter
    • On the basolateral membranes but not the canalicular domain of hepatocytes
  • Transports compounds from the blood into the liver
    • Cleared from the body
  • Most abundant uptake transporter in liver tissue
  • V jednom článku se zmiňuje i možný vliv na intestinal absorption of some drugs

Substráty SLCO1B1

  • Co vše může špatně metabolizovat / může se hromadit v těle, pokud to nemá alternativní cestu ven
  • OATP1B1 protein transports

Bilirubin

  • Yellowish substance
  • Higher affinity bilirubin uptake transporter than OATP1B3
  • Essential role in hepatic reuptake of conjugated bilirubin and uptake of unconjugated bile acids and drugs
    • pacientka homozygotka pro mutaci dysf. SLCO1B1 by tedy mohla mít + urobilinogen v moči

Hormones

  • Sulfation is an important pathway in the metabolism of thyroid hormone and estrogens
    • Reversible by estrogen sulfatase
    • Sulfation of thyroid hormone accelerates its degradation by the type 1 deiodinase in liver
  • Organic anion transporters (OATPs) are capable of transporting - candidate is OATP1B1
    • Iodothyronine sulfates such as
      • T4 sulfate (T4S),
      • T3S,
      • RT3S
    • estrogen sulfates like
      • Estrone sulfate (E1S), estrone-3-sulfate
  • Takže asi bude pacientka s mutací ciltivější na substituci hormony štítné žlázy - ke korekci jí bude stačit asi nižší dávka a v případě hormonální anitkoncepce jí budou stačit mnohem nižší dávky

Toxins

Heart disease medications

Certain antibiotics

Some anitcancer drugs

Ezetimibe

  • Gene-dose-dependent decrease in the area under the curve of ezetimibe in participants with the OATP1B1*1b protein
    • *1a/*1a, N=12, 112+/-66 ngxh/ml
    • Vs. *1a/*1b, N=8, 88+/-39 ngxh/ml
    • Vs. *1b/*1b, N=5, 55+/-18 ngxh/ml; Jonkheere-Terpstra, P=0.041
  • Tendency for increased glucuronide exposure
    • 704+/-296
    • Vs. 878+/-369
    • Vs. 1059+/-363 ngxh/ml; P=0.092
  • Fecal ezetimibe excretion was significantly decreased
  • Whereas renal glucuronide excretion was increased in carriers of *1b/*1b
  • Fecal excretion was also diminished in carriers of OATP1B1*5 and *15
  • The sterol-lowering effect of ezetimibe was not influenced by OATP1B1 polymorphisms.
  • Chápu dobře, že ze střeva vstřebaný ezetimib do jater ve své lipofilní podobě vstoupí, pak je problém až s vyloučením glukuronidované formy ? Ta pak může jít močí ? Jak moc by tedy pro tyto pacienty byl Ezetimib toxický? Směla by ho paní užívat v malé dávce, či nikoliv ?

Statiny

  • Pokud odbře chápu, tak nejen, že hrozí kumulace statinů v těle a nežádoucí účinky ve svalovině aj., ale tím, že do jater vstupují špatně, tak ani účinek na snižení syntézy chlesterolu nebude nijak zvlášť silný (odtud ten termín "slow responders to pravastatin" nenbo jak to přesně bylo)
    • potvrzení nacházím zde:
      • Pravastatin, atorvastatin, simvastatin in "oatp1a/1b-knockout mice exhibited 1.6- to 19-fold increased intravenous and 2.1- to 115-fold increased oral drug exposure, due to 33%-75% decreased clearance, 14%-60% decreased volume of distribution, and ?74-fold increased oral bioavailability, with the magnitude of change depending on the contribution of oatp1a/1b to pharmacokinetics. Hepatic drug distribution was 4.2- to 196-fold lower in oatp1a/1b-knockout mice;"
    • www.ncbi.nlm.nih.gov/pubmed/24194513
  • Atorvastatin
  • Fluvastatin
  • Pitavastatin
    • Predominant transporter for the hepatic uptake is OATP1B1
  • Simvastatin
    • "active simvastatin acid from portal circulation into the liver, resulting in markedly increased plasma concentrations of simvastatin acid and an enhanced risk of simvastatin-induced myopathy"
    • www.ncbi.nlm.nih.gov/pubmed/19785645
  • Clearances atorvastatin, pravastatin, rosuvastatin, and simvastatin
    • OATP1B1 and OATP1B3 were major contributors
    • Other statins, the net hepatic uptake clearance was underpredicted
      • Suggesting the involvement of other hepatic uptake transporters
        (tohle by mohlo být možná zajímavé)
    • www.ncbi.nlm.nih.gov/pubmed/24989890

Metformin - antidiabetikum

Repaglinide - antidiabetikum

Fexofenadine - anithistaminikum

Atrasentan - endothelin A receptor antagonist

Enalapril

Methotrexate

  • "data demonstrate a marked and possibly rate-limiting role for human OATP1B1 in MTX elimination in vivo. Variation in OATP1B1 activity due to genetic polymorphisms, drug-drug interactions, and possibly dietary conditions may therefore play a role in the severity of MTX-related toxicity."
  • Intestinal absorption of oral methotrexate or fexofenadine was not affected in Slco1a/1b-/- mice
  • Rifampicin was an effective and specific Oatp1a/1b inhibitor in controlling methotrexate pharmacokinetics
  • Když si maminka užívající metotrexát dala resveratrol a Detralex, objevili se jí mnohočetné afty v puse jako projev toxicity metotrexatu

OATP1B1 inhibitors

  • Large number of therapeutic reagents are substrates and/or inhibitors of OATP1B1 and OATP1B3
  • Inhibition of OATP1B1 is an important mechanism for drug-induced unconjugated hyperbilirubinemia
    • Předpokládám, že když je pacientka homozygotka pro mutaci v OATP1B1 transportéru, tak kompenzačně bilirubin více odstraňuje OATP1B3 a díky tomu nemá na první pohled žádnou viditelnou žloutenku (jenom oranžová xantalesmata) a že tedy blokátory OATP1B3 u ní mohou způsobit viditelnou žloutenku pak velmi výrazně

Gemfibrozil

  • Displays DDIs with some OATP1B1 substrates, although their extent is small

Rifampicin

Some HIV protease inhibitors

Indinavir

Saquinavir

Cyclosporin A

ATB

  • Four antibiotics inhibited OATP1B1-mediated transport
  • 11 antibiotics inhibited OATP1B3-mediated transport in a concentration-dependent manner
    • clarithromycin
    • Rifampicin and penicillin were transported by both OATP1B1 and OATP1B3
  • OATP1B3 was involved in the transport of
    • Ceftriaxone, cefmetazole, cefoperazone, and cefotaxime
  • Macrolides were not significantly transported by either transporter

Sekundární metabolity rostlin

  • Inhibitors of the OATP1B1, OATP1B3, and OCT1 transport activity

Ginkgo biloba flavonoids

  • Competitive inhibition of the OATP1B1- and OATP1B3

Apigenin,

  • Inhibition of the OATP1B1-mediated [3H]atorvastatin transport, apigenin was the most potent inhibitor

Kaempferol,

Quercetin,

  • Most potent inhibitor of the OATP1B1- and OATP1B3 mediated [3H]BSP transport

Grapefruit flavonoids

  • Naringenin, naringin
    • Naringenin was the most potent inhibitor of the OATP1B1- and OATP1B3-mediated [3H]BSP transport

Rutin

Estrone-3-sulfate (OATP1B1/OATP2B1 inhibitor)

Estradiol-17beta-D-glucuronide (OATP1B1/OATP1B3 inhibitor)

Advanced liver diseases

  • Snížení exprese of the OATP1B proteins in advanced liver diseases
    • Inversely correlated with serum bilirubin levels
    • More pronounced in advanced primary biliary diseases (1.9±1.1 vs. 2.7±0.6; P=0.009).
      • Down-regulation of OATP1B proteins may contribute to pathogenesis of jaundice accompanying advanced cholestatic liver diseases.
    • www.ncbi.nlm.nih.gov/pubmed/26191226

Digitoxin and digitoxigenin

Somatostatin analog octreotide

  • Can lead to hyperbilirubinemia without evidence of liver injury
  • Inhibits the main sinusoidal/canalicular bilirubin carriers
    • OATP1B1-mediated transport and weaker inhibition for OATP1B3- and MRP2-mediated transport
    • no effect on OATP2B1-mediated transport
    • Inhibited [(3)H]estradiol-17-ß-glucuronide (E17ßG) influx mediated by OATP1B1, 1B3, and multidrug resistance-associated protein 2 (MRP2) in a concentration-dependent manner
      • Inhibition of [(3)H]E17ßG OATP1B1-mediated transport was purely competitive
    • www.ncbi.nlm.nih.gov/pubmed/26330539

Chronic kidney disease (CKD)

  • Reduced OATP1B1 and OATP1B3 activity
  • Four uremic toxins inhibited OATP1B1- and OATP1B3-mediated transport in a concentration-dependent manner

Nealkoholická jaterní steatóza


Stimulace transportu

  • Human embryonic kidney cells stably expressing OATP1B1 or OATP1B3
    • NSAIDs + paracetamol interact with OATP1B1 and OATP1B3
    • Bromosulfophthalein uptake was inhibited by
      • Diclofenac,
      • Ibuprofen
      • Lumiracoxib
    • Pravastatin uptake was stimulated by
      • NSAIDs
      • Ibuprofen - activation constants (EC50 values) of 64.0 and 93.1 µM for OATP1B1- and OATP1B3-mediated uptake
    • Diclofenac
      • Was significantly transported by OATP1B3
  • All other NSAIDs investigated

Mutations in the SLCO1B1

  • Increases the plasma concentrations of OATP1B1 substrates
  • Markedly increased plasma concentrations of, for example, many statins, particularly of active simvastatin acid.

Mutace SLCO1B1 a SLCO1B3

Rotor syndrome

  • Elevated levels of bilirubin in the blood
  • Cause yellowing of the skin and whites of the eyes (jaundice)
    • Odmínkou mutatace in the SLCO1B1 gene and a related gene called SLCO1B3
      • protein called OATP1B3
        • Similar transport function to OATP1B1
  • Deletion of genetic material that removes parts of both the SLCO1B1 and SLCO1B3 genes
    • no functional OATP1B1 or OATP1B3 protein is made
  • Most mutations that cause Rotor syndrome lead to
    • Abnormally short, nonfunctioning OATP1B1 and OATP1B3 proteins
  • SLCO1B1 and SLCO1B3 (605495) genes encode proteins expressed at the hepatic sinusoidal membrane
    • Effectively reabsorb bilirubin glucuronides from plasma into the liver
  • ABCC3 (604323), SLCO1B1, and SLCO1B3
    • May form a liver-blood shuttling loop for bilirubin glucuronide [2]
  • Coproporphyrinuria, an elevated urinary excretion of coproporphyrins I and III
  • The OATP1B-mediated transport of each coproporphyrin was inhibited by rifampicin.
  • Mohla by být přítomna
    • Delayed plasma clearance of an anionic diagnostic dye (bromsulfthalein)
    • Increased urinary excretion of coproporphyrin I
    • Increased risk for drug toxicity
      • Involved in the clearance of drug conjugates [2]

V174A or SLCO1B1*5

  • Common variations in the SLCO1B1 gene
  • Associated with a reduced ability to process certain drugs, including statins
  • Cca in 15 % of the population
  • Changes a single protein building block in the OATP1B1 protein
    • valine at position 174 is replaced with the amino acid alanine (written as V174A or SLCO1B1*5)
  • Less able to transport compounds into the liver
    • Elevated levels of the compounds in the body
  • Statins not efficiently transported into the liver
    • Build up in the body
    • Can cause a condition known as statin-induced myopathy
    • Causes fatigue, pain, tenderness, weakness, and cramping in muscles
    • People with the V174A polymorphism who take statin drugs have an increased risk of developing statin-induced myopathy. [1]
  • Methotrexate increase the risk of gastrointestinal toxicity by methotrexate in the treatment of children with acute lymphoblastic leukemia.
  • Two Caucasian populations (155 blood donors and 1012 participants of the Rotterdam Scan Study)
    • Genotyped for the OATP1B1-Val174Ala polymorphism and associated with bilirubin, E1S, and T4S levels
      • OATP1B1-Val174 showed a 40% higher induction of transport and metabolism of these substrates than OATP1B1-Ala174
    • Carriers of the OATP1B1-Ala174 allele had higher serum
    • www.ncbi.nlm.nih.gov/pubmed/18499754

Variants in the SLCO1B1 gene

  • Takane et al. (2006) genotyped 33 hypercholesterolemic patients
  • Analyzed their response to the cholesterol-lowering drug pravastatin

SLCO1B1*15 allele

  • Had significantly smaller reductions in total and LDL cholesterol than noncarriers at 8 weeks
  • no significant differences at 1 year posttreatment
  • SLCO1B1*15 allele is associated with a slow response to pravastatin (Takane et al.; 2006) [2]
  • Significant association between common variants in the SLCO1B1 gene and statin-induced myopathy
    • SEARCH Collaborative Group (2008) [2]

rs4363657

  • 85 individuals with myopathy identified
  • Noncoding SNP in intron 11 of the SLCO1B1 gene (rs4363657)
  • Nearly complete LD with the rs4149056 polymorphism (521T>C, V174A) (r2 > 0.95)
  • Identified as the only strong SNP marker associated with simvastatin-induced myopathy
  • Odds ratio (OR) for myopathy was reported as 4.3 per copy of the C allele, and 17.4 in CC homozygotes compared with TT homozygotes [4]

rs4149056 - *5 allele

  • Myopathy and a nonsynonymous SNP in exon 6 (rs4149056)
  • Odds ratio for myopathy was 4.5 per copy of the C allele and 16.9 among CC homozygotes
    • As compared with TT homozygotes (p = 2 x 10(-9))
  • Odds ratio decreased to 2.6 per C allele
  • Risk of myopathy may be substantially increased in patients who take
    • 80 mg of simvastatin daily
    • As well as in those who are also receiving certain other drugs [2]
  • More than 60% of myopathies in simvastatin 80-mg therapy were attributable to the rs4149056 C variant in SLCO1B1 in the SEARCH trial [4]
  • "This gene-statin interaction (of increased adverse events in carriers compared with noncarriers of SLCO1B1*5 allele upon statin therapy) was seen with simvastatin and atorvastatin therapy but not with pravastatin therapy" [4]
    www.sciencedirect.com/science/article/pii/B9781455701018000047

rs11045849

  • Rifampin has concentration-dependent activity against Mycobacterium tuberculosis
    • Marked variation of rifampin concentration occurs among individuals
    • Decreased response to therapy at African sites compared with non-African sites
  • Results in a P155T substitution
  • 463CA genotype was more frequent among Africans and individuals of African descent than non-Africans (24% vs 10% )

c.521T>C

  • Generally decreased hepatic uptake activity
    • SLCO1B1 521 T>C mutation provides protection for neonatal hyperbilirubinemia in Chinese neonates,
      • But not in white, Thai, Brazilian, or Malaysian populations [3]
  • Carriers of the T521C SNP were shown to have an OR of 8.86 (P < .01) for statin-induced serum creatine kinase elevation, whereas the impact of the A388G SNP was much smaller (OR of 0.24, P < .05) [4]
  • Both the 521T>C SNP and SLCO1B1*17 haplotype had been shown to be associated with increased pravastatin concentrations and decreased efficacy [4]

Homozygoté 521T>C variant

  • Simvastatin acid
    • Having more than two–three-fold increased systemic exposure compared to the other two genotypes
      • Potentially resulting in increased toxicity [4]
    • Decreased intracellular concentration of simvastatin acid for inhibiting HMG-CoA reductase in hepatocytes

c.388A>G

  • Tended to slightly increase it
    • www.ncbi.nlm.nih.gov/pubmed/25747975
    • 388 G>A mutation of the SLCO1B1 gene is a risk factor for developing neonatal hyperbilirubinemia in Chinese neonates,
      • But not in white, Thai, Brazilian, or Malaysian populations [3]
Literatura:

[1] ghr.nlm.nih.gov/gene/SLCO1B1#conditions
[2] omim.org/entry/604843
[3] www.scielo.br/scielo.php?pid=S0021-75572013000500004&script=sci_arttext&tlng=en
[4] www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/slco1b1
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Poslední aktualizace: 16. 6. 2019 15:34:56