Impact of physiological, pathological and environmental factors on the expression and activity of human cytochrome P450 2D6 and implications in precision medicine
被引:50
作者:
He, Zhi-Xu
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Guizhou Med Univ, Stem Cell & Tissue Engn Res Ctr, Guizhou Prov Key Lab Regenerat Med, Guiyang, Guizhou, Peoples R China
Guizhou Med Univ, Sino US Joint Lab Med Sci, Guiyang, Guizhou, Peoples R ChinaGuizhou Med Univ, Stem Cell & Tissue Engn Res Ctr, Guizhou Prov Key Lab Regenerat Med, Guiyang, Guizhou, Peoples R China
He, Zhi-Xu
[1
,2
]
Chen, Xiao-Wu
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Southern Med Univ, Dept Gen Surg, Peoples Hosp Shunde 1, Foshan, Guangdong, Peoples R ChinaGuizhou Med Univ, Stem Cell & Tissue Engn Res Ctr, Guizhou Prov Key Lab Regenerat Med, Guiyang, Guizhou, Peoples R China
Chen, Xiao-Wu
[3
]
Zhou, Zhi-Wei
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Univ S Florida, Coll Pharm, Dept Pharmaceut Sci, Tampa, FL USAGuizhou Med Univ, Stem Cell & Tissue Engn Res Ctr, Guizhou Prov Key Lab Regenerat Med, Guiyang, Guizhou, Peoples R China
Zhou, Zhi-Wei
[4
]
Zhou, Shu-Feng
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Guizhou Med Univ, Stem Cell & Tissue Engn Res Ctr, Guizhou Prov Key Lab Regenerat Med, Guiyang, Guizhou, Peoples R China
Guizhou Med Univ, Sino US Joint Lab Med Sci, Guiyang, Guizhou, Peoples R China
Univ S Florida, Coll Pharm, Dept Pharmaceut Sci, Tampa, FL USAGuizhou Med Univ, Stem Cell & Tissue Engn Res Ctr, Guizhou Prov Key Lab Regenerat Med, Guiyang, Guizhou, Peoples R China
Zhou, Shu-Feng
[1
,2
,4
]
机构:
[1] Guizhou Med Univ, Stem Cell & Tissue Engn Res Ctr, Guizhou Prov Key Lab Regenerat Med, Guiyang, Guizhou, Peoples R China
[2] Guizhou Med Univ, Sino US Joint Lab Med Sci, Guiyang, Guizhou, Peoples R China
[3] Southern Med Univ, Dept Gen Surg, Peoples Hosp Shunde 1, Foshan, Guangdong, Peoples R China
[4] Univ S Florida, Coll Pharm, Dept Pharmaceut Sci, Tampa, FL USA
With only 1.3-4.3% in total hepatic CYP content, human CYP2D6 can metabolize more than 160 drugs. It is a highly polymorphic enzyme and subject to marked inhibition by a number of drugs, causing a large interindividual variability in drug clearance and drug response and drug-drug interactions. The expression and activity of CYP2D6 are regulated by a number of physiological, pathological and environmental factors at transcriptional, post-transcriptional, translational and epigenetic levels. DNA hypermethylation and histone modifications can repress the expression of CYP2D6. Hepatocyte nuclear factor-4 binds to a directly repeated element in the promoter of CYP2D6 and thus regulates the expression of CYP2D6. Small heterodimer partner represses hepatocyte nuclear factor-4-mediated transactivation of CYP2D6. GW4064, a farnesoid X receptor agonist, decreases hepatic CYP2D6 expression and activity while increasing small heterodimer partner expression and its recruitment to the CYP2D6 promoter. The genotypes are key determinants of interindividual variability in CYP2D6 expression and activity. Recent genome-wide association studies have identified a large number of genes that can regulate CYP2D6. Pregnancy induces CYP2D6 via unknown mechanisms. Renal or liver diseases, smoking and alcohol use have minor to moderate effects only on CYP2D6 activity. Unlike CYP1 and 3 and other CYP2 members, CYP2D6 is resistant to typical inducers such as rifampin, phenobarbital and dexamethasone. Post-translational modifications such as phosphorylation of CYP2D6 Ser135 have been observed, but the functional impact is unknown. Further functional and validation studies are needed to clarify the role of nuclear receptors, epigenetic factors and other factors in the regulation of CYP2D6.
机构:
Univ Milan, Div Gastroenterol 1, Fdn IRCCS Ca Granda Osped Maggiore Policlin, AM & A Migliavacca Ctr Liver Dis,Dept Med, I-20122 Milan, ItalyUniv Milan, Div Gastroenterol 1, Fdn IRCCS Ca Granda Osped Maggiore Policlin, AM & A Migliavacca Ctr Liver Dis,Dept Med, I-20122 Milan, Italy
Aghemo, Alessio
;
Colombo, Massimo
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Univ Milan, Div Gastroenterol 1, Fdn IRCCS Ca Granda Osped Maggiore Policlin, AM & A Migliavacca Ctr Liver Dis,Dept Med, I-20122 Milan, ItalyUniv Milan, Div Gastroenterol 1, Fdn IRCCS Ca Granda Osped Maggiore Policlin, AM & A Migliavacca Ctr Liver Dis,Dept Med, I-20122 Milan, Italy
机构:
Chonnam Natl Univ, Coll Vet Med, Dept Biochem, Kwangju 500757, South KoreaChonnam Natl Univ, Coll Vet Med, Dept Biochem, Kwangju 500757, South Korea
机构:
King Abdulaziz Univ, Fac Med, Dept Clin Biochem, Jeddah 21483, Saudi ArabiaKing Abdulaziz Univ, Fac Med, Dept Clin Biochem, Jeddah 21483, Saudi Arabia
机构:
Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil
Antunes, Natalicia de Jesus
;
Cavalli, Ricardo Carvalho
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Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Gynecol & Obstet, BR-14040903 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil
Cavalli, Ricardo Carvalho
;
Marques, Maria Paula
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Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil
Marques, Maria Paula
;
Dantas Moises, Elaine Christine
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Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Gynecol & Obstet, BR-14040903 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil
Dantas Moises, Elaine Christine
;
Lanchote, Vera Lucia
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Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil
机构:
Univ Milan, Div Gastroenterol 1, Fdn IRCCS Ca Granda Osped Maggiore Policlin, AM & A Migliavacca Ctr Liver Dis,Dept Med, I-20122 Milan, ItalyUniv Milan, Div Gastroenterol 1, Fdn IRCCS Ca Granda Osped Maggiore Policlin, AM & A Migliavacca Ctr Liver Dis,Dept Med, I-20122 Milan, Italy
Aghemo, Alessio
;
Colombo, Massimo
论文数: 0引用数: 0
h-index: 0
机构:
Univ Milan, Div Gastroenterol 1, Fdn IRCCS Ca Granda Osped Maggiore Policlin, AM & A Migliavacca Ctr Liver Dis,Dept Med, I-20122 Milan, ItalyUniv Milan, Div Gastroenterol 1, Fdn IRCCS Ca Granda Osped Maggiore Policlin, AM & A Migliavacca Ctr Liver Dis,Dept Med, I-20122 Milan, Italy
机构:
Chonnam Natl Univ, Coll Vet Med, Dept Biochem, Kwangju 500757, South KoreaChonnam Natl Univ, Coll Vet Med, Dept Biochem, Kwangju 500757, South Korea
机构:
King Abdulaziz Univ, Fac Med, Dept Clin Biochem, Jeddah 21483, Saudi ArabiaKing Abdulaziz Univ, Fac Med, Dept Clin Biochem, Jeddah 21483, Saudi Arabia
机构:
Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil
Antunes, Natalicia de Jesus
;
Cavalli, Ricardo Carvalho
论文数: 0引用数: 0
h-index: 0
机构:
Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Gynecol & Obstet, BR-14040903 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil
Cavalli, Ricardo Carvalho
;
Marques, Maria Paula
论文数: 0引用数: 0
h-index: 0
机构:
Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil
Marques, Maria Paula
;
Dantas Moises, Elaine Christine
论文数: 0引用数: 0
h-index: 0
机构:
Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Gynecol & Obstet, BR-14040903 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil
Dantas Moises, Elaine Christine
;
Lanchote, Vera Lucia
论文数: 0引用数: 0
h-index: 0
机构:
Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, BrazilUniv Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil