UGT1A3 lactonizes 4-OH-ATV to 4-OH-ATVL

Stable Identifier
R-HSA-9756183
Type
Reaction [uncertain]
Species
Homo sapiens
Compartment
endoplasmic reticulum membrane, cytosol
ReviewStatus
5/5
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UGT1A3 lactonizes 4-OH-ATV to 4-OH-ATVL
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The acid form of 4-hydroxyatorvastatin (4-OH-ATV) can be converted to its lactone form (4-OH-ATVL) primarily by UDP-glucuronosyltransferase 1A3 (UGT1A3), with small contributions from UGT1A1 and 2B7 (Prueksaritanont et al. 2002, Schirris et al. 2015). The lactonization process involves the formation of an unstable acyl glucuronide intermediate (not described here). Increased generation of ATVL due to polymorphisms in UGT1A1, 1A3, and 2B7 may be contributing factors in statin-induced myopathies (Riedmaier et al. 2010). In vitro, the lactone forms of ATV show a higher potency to induce myotoxicity in human skeletal cells than their acid counterparts (Skottheim et al. 2008, Cho et al. 2012). Carriers of less strongly expressed alleles of UGT enzymes may have decreased exposure to the suspected muscle-toxic metabolite atorvastatin lactone (Stormo et al. 2013).
Literature References
PubMed ID Title Journal Year
11950779 Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization

Prueksaritanont, T, Subramanian, R, Fang, X, Ma, B, Qiu, Y, Lin, JH, Pearson, PG, Baillie, TA

Drug Metab Dispos 2002
19794410 UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo

Riedmaier, S, Klein, K, Hofmann, U, Keskitalo, JE, Neuvonen, PJ, Schwab, M, Niemi, M, Zanger, UM

Clin Pharmacol Ther 2010
26412035 Statin Lactonization by Uridine 5'-Diphospho-glucuronosyltransferases (UGTs)

Schirris, TJ, Ritschel, T, Bilos, A, Smeitink, JA, Russel, FG

Mol Pharm 2015
Participants
Input
Output
Participates
as an event of
Catalyst Activity

glucuronosyltransferase activity of UGT1A3 [endoplasmic reticulum membrane]

Physical Entity
UGT1A3 [endoplasmic reticulum membrane] (Homo sapiens)
Activity
glucuronosyltransferase activity (GO:0015020)
Orthologous Events
UGT1A3 lactonizes 4-OH-ATV to 4-OH-ATVL (Mus musculus)
UGT1A3 lactonizes 4-OH-ATV to 4-OH-ATVL (Rattus norvegicus)
Authored
Jassal, B  (2021-10-12)
Reviewed
Huddart, R  (2022-03-01)
Created
Jassal, B  (2021-10-12)
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