A Novel Variant Allele of OATP-C (SLCO1B1) Found in a Japanese Patient with Pravastatin-induced Myopathy

doi:10.2133/dmpk.19.453

Drug Metabolism and Pharmacokinetics

Volume 19, Issue 6, 2004, Pages 453-455

https://doi.org/10.2133/dmpk.19.453 Get rights and content

Summary:

We have recently found that the frequency of OATP-C*15 is significantly higher in patients who experienced myopathy after receiving pravastatin or atorvastatin than in patients without myopathy. However, there were two patients who experienced pravastatin-induced myopathy despite the fact that they did not possess OATP-C*15 or other known mutations of OATP-C that have been reported to decrease the function of OATP-C. In this study, we sequenced all of the exons and exonintron junctions of OATP-C of the two patients and found a novel mutation in exon 12 of OATP-C in one of the patients. In this mutation (1628T>G), there is a substitution of Leu to Trp at position 543 in transmembrane-spanning domain 10 of OATP-C. However, the frequency of this mutation in the Japanese population appears to be very low (< 1%).

References (9)

R.G. Tirona et al.
Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European-and African-Americans
J. Biol. Chem.
(2001)
T. Abe et al.
Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1
J. Biol. Chem.
(1999)
E.J. Topol
Intensive statin therapy—a sea change in cardiovascular prevention
N. Engl. J. Med.
(2004)
P.D. Thompson et al.
Statinassociated myopathy
Jama
(2003)

There are more references available in the full text version of this article.

Cited by (91)

Biomarkers of Drug Toxicity and Safety Evaluation
2019, Biomarkers in Toxicology
Some compounds can fail in the latter stages of development because of lack of efficacy and toxicity. To improve drug safety in the development, new biomarkers are needed, which can reduce the time-consuming process and cost of drug development. Traditional indicators of target organ toxicity used in drug preclinical safety studies are described. Severe adverse drug reactions are a major issue for drug therapy because they can cause serious disorders and be life-threatening. There is need for new efficient biomarkers of drug toxicity, which some of them can translate effectively from preclinical studies, and an important number of the biomarkers are described in this chapter. The safety biomarker should be validated and preclinical and clinical qualified. Several urinary kidney biomarkers in the context of preclinical development and clinical trials are presented in this chapter. Application of safety biomarkers in different phases of drug development is described.
Uptake Transporters
2018, Comprehensive Toxicology: Third Edition
Membrane transporters are recognized to be an important class of proteins for regulating cellular and physiologic solute and fluid balance. Transporter proteins can be generally separated into two major classes—uptake and efflux transporters. Not only are transporter proteins critical to human physiology in the maintenance of normal homeostasis via transport of endogenous substrates, but they are also, in many cases, important to the disposition of numerous xenobiotic compounds such as environmental toxins, dietary constituents, drugs, and their metabolites. In particular, over the past two decades, members of the solute carrier (SLC) families, including the organic anion transporting polypeptide (SLCO) family, the organic cation/anion/zwitterion transporter (SLC22) family, and the sodium bile salt cotransport (SLC10) family, have been determined to have important physiological, pathological, and therapeutic implications. In this article, we focus on uptake transporter proteins and provide a comprehensive overview of the significant roles these proteins play in normal physiology and the drug disposition process.
Mechanism of action of anti-hypercholesterolemia drugs and their resistance
2014, European Journal of Pharmacology
Coronary artery disease is one of the leading causes of death worldwide. One of the significant causes of this disease is hypercholesterolemia which is the result of various genetic alterations that are associated with the accumulation of specific classes of lipoprotein particles in plasma. A number of drugs are used to treat hypercholesterolemia like statin, fibrate, bile acid sequestrants, niacin, ezetimibe, omega-3 fatty acids and natural extracts. It has been observed that these drugs show diverse response in different individuals. The present review explains the mechanism of action of these drugs as well as mechanism of its lesser effectiveness or resistance in some individuals. There are various identified genetic variations that are associated with diversity in the drugs response. Therefore, present study helps to understand the ethiology of drug mechanism and resistance developed against drugs used to treat hypercholesterolemia.
Inherited disorders of bilirubin transport and conjugation: New insights into molecular mechanisms and consequences
2014, Gastroenterology
Citation Excerpt :
OATP1B1 plays a major role in drug detoxification. Indeed, reduced-activity OATP1B1 polymorphisms have been shown to reduce drug transport and increase plasma and tissue concentrations of drugs such as anticancer agents, methotrexate, and statins, potentially resulting in toxicity.30–33 Even if no drug accumulation or toxicity has so far been reported in patients with RS, it is advisable to take these findings into account, especially in patients with RS who have jaundice.
Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of unconjugated or conjugated bilirubin (Rotor syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler–Najjar syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin–Johnson syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic syndrome and the effects of specific genetic variants on drug metabolism and cancer development.
Membrane transporters and transporter substrates as biomarkers for drug pharmacokinetics, pharmacodynamics, and toxicity/adverse events
2014, Biomarkers in Toxicology
Membrane transporters belong to two major super families, ATP binding cassette (ABC) transporters and solute carriers (SLC), and play a central role in body homeostasis regulation. Among these membrane proteins, the transporters carrying drugs are extensively studied and participate into the protection of the body against xenobiotics. Drug transporters are involved in all aspects of drugs absorption, disposition, and excretion. Several ABC transporters are highly overexpressed in various tumors and play an important role in the development of multidrug resistance phenotypes in cancers. Furthermore, several transporter polymorphisms have been shown to alter the pharmacokinetic profile of drugs in clinics. Drug transporters are, therefore, biomarkers of drug pharmacodynamics and pharmacokinetics. Finally, transporter substrates can also serve as biomarkers when transporter function is impaired. This chapter reviews the recent research progress in this field with an emphasis on the use of drug transporters as biomarkers in clinics.
Biomarkers of drug toxicity
2014, Biomarkers in Toxicology
Severe adverse drug reactions (ADRs) are a major issue for drug therapy because they can cause serious disorders and be life-threatening. The idiosyncratic reactions are unpredictable from the pharmacological action of the drug. Genes are also associated with ADRs; genes that consistently exhibit increased or decreased expression during these toxic responses in model systems serve as biomarkers to predict potential adverse effects. Hepatotoxicity and nephrotoxicity are two major reasons that drugs are withdrawn post-market. Other important ADRs affect blood vessels, heart, and brain. There are high risks for ADRs in the acetaminophen hepatotoxicity and with antitubercular and antiretroviral drug-induced liver injury when they are indicated in HIV patients. There is need for new efficient biomarkers of drug toxicity, and some of them can translate effectively from preclinical studies. An important number of biomarkers are described in this chapter. Nowadays the circulating microRNAs represent a class of tissue-specific blood-based biomarkers that are useful in clinical toxicity.

View all citing articles on Scopus

: Until October 11, 2004, the mutation described herein has not been registered in the NCBI dbSNP or JSNP database

View full text

SNP CommunicationA Novel Variant Allele of OATP-C (SLCO1B1) Found in a Japanese Patient with Pravastatin-induced Myopathy

Summary:

J. Biol. Chem.

J. Biol. Chem.

Intensive statin therapy—a sea change in cardiovascular prevention

N. Engl. J. Med.

Statinassociated myopathy

Jama

SNP Communication
A Novel Variant Allele of OATP-C (SLCO1B1) Found in a Japanese Patient with Pravastatin-induced Myopathy