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{{PBB|geneid=5444}}
{{PBB|geneid=5444}}
'''Serum paraoxonase/arylesterase 1''' ('''PON1''') also known as '''aromatic esterase 1''' or '''serum aryldialkylphosphatase 1''' is an [[enzyme]] that in humans is encoded by the ''PON1'' [[gene]].<ref name="pmid8661009">{{cite journal | author = Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN | title = The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family | journal = Genomics | volume = 33 | issue = 3 | pages = 498–507 |date=May 1996 | pmid = 8661009 | doi = 10.1006/geno.1996.0225 | url = }}</ref> Paraoxonase 1 has [[esterase]] and more specifically [[paraoxonase]] activity.<ref name="pmid16517986">{{cite journal | author = van Himbergen TM, van Tits LJ, Roest M, Stalenhoef AF | title = The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine | journal = Neth J Med | volume = 64 | issue = 2 | pages = 34–8 |date=February 2006 | pmid = 16517986 | doi = | url = http://www.zuidencomm.nl/njm/getarticle.php?v=64&i=2&p=34 | issn = }}</ref>
'''Serum paraoxonase/arylesterase 1''' ('''PON1''') also known as '''aromatic esterase 1''' or '''serum aryldialkylphosphatase 1''' is an [[enzyme]] that in humans is encoded by the ''PON1'' [[gene]].<ref name="pmid8661009">{{cite journal | author = Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN | title = The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family | journal = Genomics | volume = 33 | issue = 3 | pages = 498–507 |date=May 1996 | pmid = 8661009 | doi = 10.1006/geno.1996.0225 | url = }}</ref> Paraoxonase 1 has [[esterase]] and more specifically [[paraoxonase]] activity.<ref name="pmid16517986">{{cite journal | author = van Himbergen TM, van Tits LJ, Roest M, Stalenhoef AF | title = The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine | journal = Neth J Med | volume = 64 | issue = 2 | pages = 34–8 |date=February 2006 | pmid = 16517986 | doi = | url = http://www.zuidencomm.nl/njm/getarticle.php?v=64&i=2&p=34 | issn = }}</ref>


== General and Structure Characteristics ==

Serum PON1 is found in all mammalian species studied so far but is not present in the serum of birds, fish and reptiles or in insects. PON1 is the first discovered member of a multigene family also containing PON2 and PON3, the genes for which are located adjacent to each other on chromosome 7.
Human PON1 is a glycoprotein comprised of 354 amino acids and has a molecular weight of 43000 Daltons which associates with high-density lipoprotein (HDL, "good cholesterol") in the circulation. Serum PON1 is secreted mainly by the liver although local synthesis occurs in several tissues and PON1 protein is found in almost all tissues. X-ray crystallography has revealed the structure of PON1 to be a 6 bladed propeller with a unique lid structure covering the active site passage and which allows association with HDL. The structure contains 2 calcium ions which are essential for catalytic activity and enzyme stability.<ref name=PMID15098021>{{cite journal|last1=Harel|first1=M|last2=Aharoni|first2=A|last3=Gaidukov|first3=L|last4=Brumshtein|first4=B|last5=Khersonsky|first5=O|last6=Meged|first6=R|last7=Dvir|first7=H|last8=Ravelli|first8=RB|last9=McCarthy|first9=A|last10=Toker|first10=L|last11=Silman|first11=I|last12=Sussman|first12=JL|last13=Tawfik|first13=DS|title=Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes.|journal=Nature structural & molecular biology|date=May 2004|volume=11|issue=5|pages=412-9|pmid=15098021}}</ref><ref name=PMID9703197>{{cite journal|last1=Mackness|first1=B|last2=Durrington|first2=PN|last3=Mackness|first3=MI|title=Human serum paraoxonase.|journal=General pharmacology|date=September 1998|volume=31|issue=3|pages=329-36|pmid=9703197}}</ref><ref name=PMID15265000>{{cite journal|last1=Deakin|first1=SP|last2=James|first2=RW|title=Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1.|journal=Clinical science (London, England : 1979)|date=November 2004|volume=107|issue=5|pages=435-47|pmid=15265000}}</ref>

⚫
Its 3D structure was determined in 2004 and revealed that it is a six-bladed beta-propeller with a unique active site lid that is also involved in HDL binding.<ref name="pmid15098021">{{cite journal | author = Harel M, Aharoni A, Gaidukov L, Brumshtein B, Khersonsky O, Meged R, Dvir H, Ravelli RB, McCarthy A, Toker L, Silman I, Sussman JL, Tawfik DS | title = Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes | journal = Nat Struct Mol Biol | volume = 11 | issue = 5 | pages = 412–9 | year = 2004 | pmid = 15098021 | doi=10.1038/nsmb767}}</ref>


== Function ==
== Function ==
Line 9: Line 17:
{{cite journal | author=Mackness M, Mackness B |title=Paraoxonase 1 and atherosclerosis: is the gene or the protein more important? |journal=Free Radic. Biol. Med. |volume=37 |issue= 9 |pages= 1317–23 |year= 2005 |pmid= 15454272 |doi= 10.1016/j.freeradbiomed.2004.07.034 }}</ref> The PON1 gene is activated by [[Peroxisome proliferator-activated receptor gamma|PPAR-γ]], which increases synthesis and release of [[paraoxonase]]&nbsp;1 enzyme from the liver, reducing [[atherosclerosis]].<ref name="pmid19783251">{{cite journal | author = Khateeb J, Gantman A, Kreitenberg AJ, Aviram M, Fuhrman B | title = Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway | journal = Atherosclerosis | volume = 208 | issue = 1 | pages = 119–25 |date=January 2010 | pmid = 19783251 | doi = 10.1016/j.atherosclerosis.2009.08.051 }}</ref>
{{cite journal | author=Mackness M, Mackness B |title=Paraoxonase 1 and atherosclerosis: is the gene or the protein more important? |journal=Free Radic. Biol. Med. |volume=37 |issue= 9 |pages= 1317–23 |year= 2005 |pmid= 15454272 |doi= 10.1016/j.freeradbiomed.2004.07.034 }}</ref> The PON1 gene is activated by [[Peroxisome proliferator-activated receptor gamma|PPAR-γ]], which increases synthesis and release of [[paraoxonase]]&nbsp;1 enzyme from the liver, reducing [[atherosclerosis]].<ref name="pmid19783251">{{cite journal | author = Khateeb J, Gantman A, Kreitenberg AJ, Aviram M, Fuhrman B | title = Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway | journal = Atherosclerosis | volume = 208 | issue = 1 | pages = 119–25 |date=January 2010 | pmid = 19783251 | doi = 10.1016/j.atherosclerosis.2009.08.051 }}</ref>


The "natural" substrates for PON1 appear to be lactones <ref name=Mack10>{{cite journal|last1=Khersonsky|first1=O|last2=Tawfik|first2=DS|title=Structure-reactivity studies of serum paraoxonase PON1 suggest that its native activity is lactonase.|journal=Biochemistry|date=26 April 2005|volume=44|issue=16|pages=6371-82|pmid=15835926}}</ref>. However, PON1 has evolved to be a highly promiscuous enzyme capable of hydrolysing a wide variety of substrates such as lactones (including a number of important pharmaceutical agents such as statins), glucuronide drugs, thiolactones, arylesters, cyclic carbonates, organophosphorus pesticides and nerve gases such as sarin, soman and VX, oestrogen esters and lipid-peroxides(oxidised lipids).
== Structure ==

== Genetics ==
PON1 in humans is encoded by the PON1 gene which is located on the long arm of chromosome 7 <ref name=Mack5>{{cite journal|last1=Clendenning|first1=JB|last2=Humbert|first2=R|last3=Green|first3=ED|last4=Wood|first4=C|last5=Traver|first5=D|last6=Furlong|first6=CE|title=Structural organization of the human PON1 gene.|journal=Genomics|date=1 August 1996|volume=35|issue=3|pages=586-9|pmid=8812495}}</ref>. Although many nutritional, life-style and pharmaceutical modulators of PON1 are known <ref name=Mack6>{{cite journal|last1=Costa|first1=LG|last2=Vitalone|first2=A|last3=Cole|first3=TB|last4=Furlong|first4=CE|title=Modulation of paraoxonase (PON1) activity.|journal=Biochemical pharmacology|date=15 February 2005|volume=69|issue=4|pages=541-50|pmid=15670573}}</ref> <ref name=Mack7>{{cite journal|last1=Schrader|first1=C|last2=Graeser|first2=AC|last3=Huebbe|first3=P|last4=Wagner|first4=AE|last5=Rimbach|first5=G|title=Allyl isothiocyanate as a potential inducer of paraoxonase-1--studies in cultured hepatocytes and in mice.|journal=IUBMB life|date=February 2012|volume=64|issue=2|pages=162-8|pmid=22131196}}</ref>, by far the biggest effect on PON1 activity levels, which can vary by over 40 fold between individuals, is through PON1 genetic polymorphisms <ref name=PMID9703197 />. The coding region PON1-Q192R polymorphism determines a substrate dependent effect on activity. Some substrates e.g. paraoxon are hydrolysed faster by the R- isoform while others such as diazoxon and lipid-peroxides are hydrolysed more rapidly by the Q- isoform <ref name=PMID9703197 />. Both the coding region PON1-L55M and the promoter region PON1-T-108C polymorphisms are associated with different serum concentrations and therefore activities. The 55L allele results in significantly higher PON1 mRNA and serum protein levels and therefore activity compared to the 55M allele <ref name=Mack6 /><ref name=Mack7 />.The -108C allele has greater promoter activity than the -108T allele which results in different serum activities <ref name=Mack6 /><ref name=Mack7 />.
It is worth noting that the distribution of the PON1 polymorphisms varies with ethnicity. The frequency of the PON1-192R allele increases the further from Europe a population originates, the frequency in Caucasians of 15-30% increases to 70-90% in Far Eastern Oriental and Sub-Saharan African populations <ref name=Mack8>{{cite book|last1=La Du|first1=B.N|editor1-last=Kalow|editor1-first=W|title=Pharmacogenetics of Drug Metabolism|date=1992|publisher=Pergamon Press|location=New York|page=51|pages=91|chapter=Human serum paraoxonase/arylesterase}}</ref>. In the southern USA African-Americans are 5 times more likely to be RR than Caucasians <ref name=Mack9>{{cite journal|last1=McDaniel|first1=CY|last2=Dail|first2=MB|last3=Wills|first3=RW|last4=Chambers|first4=HW|last5=Chambers|first5=JE|title=Paraoxonase 1 polymorphisms within a Mississippi USA population as possible biomarkers of enzyme activities associated with disease susceptibility.|journal=Biochemical genetics|date=December 2014|volume=52|issue=11-12|pages=509-23|pmid=25027835}}</ref>. In contrast the PON1-55M allele is much less frequent in Oriental and black African populations compared to Caucasians and are extremely rare/absent in some populations e.g. Thais. These ethnic differences in SNP distribution can lead to large activity differences between populations <ref name=Mack8 />.



⚫
Its 3D structure was determined in 2004 and revealed that it is a six-bladed beta-propeller with a unique active site lid that is also involved in HDL binding.<ref name="pmid15098021">{{cite journal | author = Harel M, Aharoni A, Gaidukov L, Brumshtein B, Khersonsky O, Meged R, Dvir H, Ravelli RB, McCarthy A, Toker L, Silman I, Sussman JL, Tawfik DS | title = Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes | journal = Nat Struct Mol Biol | volume = 11 | issue = 5 | pages = 412–9 | year = 2004 | pmid = 15098021 | doi=10.1038/nsmb767}}</ref>


== Clinical significance ==
== Clinical significance ==

PON1 was first discovered through its ability to hydrolyse and therefore detoxify organophosphorus compounds which are widely used as pesticides and nerve gases. Despite decades of research it is only now becoming clear that PON1 protects humans from the acute and chronic harmful effects of these compounds<ref name=Mack11>{{cite journal|last1=Costa|first1=LG|last2=Giordano|first2=G|last3=Cole|first3=TB|last4=Marsillach|first4=J|last5=Furlong|first5=CE|title=Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity.|journal=Toxicology|date=10 May 2013|volume=307|pages=115-22|pmid=22884923}}</ref> <ref name=Mack12>{{cite book|last1=Mackness|first1=M|last2=Mackness|first2=B|editor1-last=Komoda|editor1-first=Tsugikazu|title=The HDL handbook : biological functions and clinical implications|date=2014|publisher=Academic Press|location=Amsterdam|isbn=978-0-12-407867-3|edition=Second edition.|chapter=Current aspects of paraoxonase-1 research}}</ref>. Low PON1 activity found in children may increase their susceptibility to organophosphates.
Oxidised-lipids are the major cause of inflammation and are responsible for the initiation and/or propagation of several inflammatory diseases including atherosclerosis (heart disease and stroke), diabetes, liver and kidney diseases, rheumatic diseases, eye diseases (macular degeneration), cancer and HIV infection. Because of its ability to destroy oxidised-lipids PON1 appears to play some role in all these diseases. However, the greatest research interest has been the role of PON1 in atherosclerosis, where, because of its ability to remove harmful oxidised-lipids, PON1 protects against the development of atherosclerosis<ref name=Mack13>{{cite journal|last1=Costa|first1=LG|last2=Cole|first2=TB|last3=Jarvik|first3=GP|last4=Furlong|first4=CE|title=Functional genomic of the paraoxonase (PON1) polymorphisms: effects on pesticide sensitivity, cardiovascular disease, and drug metabolism.|journal=Annual review of medicine|date=2003|volume=54|pages=371-92|pmid=12525679}}</ref>.
PON1 also protects against bacterial infection by destroying the bacterial signalling molecules that cause gram -ve bacteria to invade human tissue and form colonies, thus PON1 contributes to the bodies innate immunity<ref name=Mack14>{{cite journal|last1=Camps|first1=J|last2=Pujol|first2=I|last3=Ballester|first3=F|last4=Joven|first4=J|last5=Simó|first5=JM|title=Paraoxonases as potential antibiofilm agents: their relationship with quorum-sensing signals in Gram-negative bacteria.|journal=Antimicrobial agents and chemotherapy|date=April 2011|volume=55|issue=4|pages=1325-31|pmid=21199929}}</ref>.
Recently it has been suggested that PON1 has a role in healthy ageing, however, the mechanism is currently unknown<ref name=MAck15>{{cite journal|last1=Lee|first1=YS|last2=Park|first2=CO|last3=Noh|first3=JY|last4=Jin|first4=S|last5=Lee|first5=NR|last6=Noh|first6=S|last7=Lee|first7=JH|last8=Lee|first8=KH|title=Knockdown of paraoxonase 1 expression influences the ageing of human dermal microvascular endothelial cells.|journal=Experimental dermatology|date=September 2012|volume=21|issue=9|pages=682-7|pmid=22897574}}</ref>.


PON1 activity is low in infants compared to adults. A study of Mexican-American children showed that PON1 activity increased 3.5 times between birth and age seven.<ref name="pmid20045427">{{cite journal | author = Huen K, Harley K, Bradman A, Eskenazi B, Holland N | title = Longitudinal changes in PON1 enzymatic activities in Mexican-American mothers and children with different genotypes and haplotypes | journal = Toxicol. Appl. Pharmacol. | volume = 244 | issue = 2 | pages = 181–9 |date=April 2010 | pmid = 20045427 | pmc = 2846980 | doi = 10.1016/j.taap.2009.12.031 }}</ref>
PON1 activity is low in infants compared to adults. A study of Mexican-American children showed that PON1 activity increased 3.5 times between birth and age seven.<ref name="pmid20045427">{{cite journal | author = Huen K, Harley K, Bradman A, Eskenazi B, Holland N | title = Longitudinal changes in PON1 enzymatic activities in Mexican-American mothers and children with different genotypes and haplotypes | journal = Toxicol. Appl. Pharmacol. | volume = 244 | issue = 2 | pages = 181–9 |date=April 2010 | pmid = 20045427 | pmc = 2846980 | doi = 10.1016/j.taap.2009.12.031 }}</ref>

Revision as of 15:41, 26 March 2015

Template:PBB Serum paraoxonase/arylesterase 1 (PON1) also known as aromatic esterase 1 or serum aryldialkylphosphatase 1 is an enzyme that in humans is encoded by the PON1 gene.[1] Paraoxonase 1 has esterase and more specifically paraoxonase activity.[2]


General and Structure Characteristics

Serum PON1 is found in all mammalian species studied so far but is not present in the serum of birds, fish and reptiles or in insects. PON1 is the first discovered member of a multigene family also containing PON2 and PON3, the genes for which are located adjacent to each other on chromosome 7. Human PON1 is a glycoprotein comprised of 354 amino acids and has a molecular weight of 43000 Daltons which associates with high-density lipoprotein (HDL, "good cholesterol") in the circulation. Serum PON1 is secreted mainly by the liver although local synthesis occurs in several tissues and PON1 protein is found in almost all tissues. X-ray crystallography has revealed the structure of PON1 to be a 6 bladed propeller with a unique lid structure covering the active site passage and which allows association with HDL. The structure contains 2 calcium ions which are essential for catalytic activity and enzyme stability.[3][4][5]

Its 3D structure was determined in 2004 and revealed that it is a six-bladed beta-propeller with a unique active site lid that is also involved in HDL binding.[6]

Function

PON1 is responsible for hydrolysing organophosphate pesticides and nerve gasses. Polymorphisms in the PON1 gene significantly affect the catalytic ability of the enzyme.[7]

PON1 (paraoxonase 1) is also a major anti-atherosclerotic component of high-density lipoprotein (HDL).[8][9] The PON1 gene is activated by PPAR-γ, which increases synthesis and release of paraoxonase 1 enzyme from the liver, reducing atherosclerosis.[10]

The "natural" substrates for PON1 appear to be lactones [11]. However, PON1 has evolved to be a highly promiscuous enzyme capable of hydrolysing a wide variety of substrates such as lactones (including a number of important pharmaceutical agents such as statins), glucuronide drugs, thiolactones, arylesters, cyclic carbonates, organophosphorus pesticides and nerve gases such as sarin, soman and VX, oestrogen esters and lipid-peroxides(oxidised lipids).

Genetics

PON1 in humans is encoded by the PON1 gene which is located on the long arm of chromosome 7 [12]. Although many nutritional, life-style and pharmaceutical modulators of PON1 are known [13] [14], by far the biggest effect on PON1 activity levels, which can vary by over 40 fold between individuals, is through PON1 genetic polymorphisms [4]. The coding region PON1-Q192R polymorphism determines a substrate dependent effect on activity. Some substrates e.g. paraoxon are hydrolysed faster by the R- isoform while others such as diazoxon and lipid-peroxides are hydrolysed more rapidly by the Q- isoform [4]. Both the coding region PON1-L55M and the promoter region PON1-T-108C polymorphisms are associated with different serum concentrations and therefore activities. The 55L allele results in significantly higher PON1 mRNA and serum protein levels and therefore activity compared to the 55M allele [13][14].The -108C allele has greater promoter activity than the -108T allele which results in different serum activities [13][14]. It is worth noting that the distribution of the PON1 polymorphisms varies with ethnicity. The frequency of the PON1-192R allele increases the further from Europe a population originates, the frequency in Caucasians of 15-30% increases to 70-90% in Far Eastern Oriental and Sub-Saharan African populations [15]. In the southern USA African-Americans are 5 times more likely to be RR than Caucasians [16]. In contrast the PON1-55M allele is much less frequent in Oriental and black African populations compared to Caucasians and are extremely rare/absent in some populations e.g. Thais. These ethnic differences in SNP distribution can lead to large activity differences between populations [15].


Clinical significance

PON1 was first discovered through its ability to hydrolyse and therefore detoxify organophosphorus compounds which are widely used as pesticides and nerve gases. Despite decades of research it is only now becoming clear that PON1 protects humans from the acute and chronic harmful effects of these compounds[17] [18]. Low PON1 activity found in children may increase their susceptibility to organophosphates. Oxidised-lipids are the major cause of inflammation and are responsible for the initiation and/or propagation of several inflammatory diseases including atherosclerosis (heart disease and stroke), diabetes, liver and kidney diseases, rheumatic diseases, eye diseases (macular degeneration), cancer and HIV infection. Because of its ability to destroy oxidised-lipids PON1 appears to play some role in all these diseases. However, the greatest research interest has been the role of PON1 in atherosclerosis, where, because of its ability to remove harmful oxidised-lipids, PON1 protects against the development of atherosclerosis[19]. PON1 also protects against bacterial infection by destroying the bacterial signalling molecules that cause gram -ve bacteria to invade human tissue and form colonies, thus PON1 contributes to the bodies innate immunity[20]. Recently it has been suggested that PON1 has a role in healthy ageing, however, the mechanism is currently unknown[21].

PON1 activity is low in infants compared to adults. A study of Mexican-American children showed that PON1 activity increased 3.5 times between birth and age seven.[22] An association between PON1 gene polymorphism and susceptibility to Parkinson's disease was not found in a Chinese population.[23]

References

  1. ^ Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN (May 1996). "The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family". Genomics. 33 (3): 498–507. doi:10.1006/geno.1996.0225. PMID 8661009.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ van Himbergen TM, van Tits LJ, Roest M, Stalenhoef AF (February 2006). "The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine". Neth J Med. 64 (2): 34–8. PMID 16517986.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Harel, M; Aharoni, A; Gaidukov, L; Brumshtein, B; Khersonsky, O; Meged, R; Dvir, H; Ravelli, RB; McCarthy, A; Toker, L; Silman, I; Sussman, JL; Tawfik, DS (May 2004). "Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes". Nature structural & molecular biology. 11 (5): 412–9. PMID 15098021.
  4. ^ a b c Mackness, B; Durrington, PN; Mackness, MI (September 1998). "Human serum paraoxonase". General pharmacology. 31 (3): 329–36. PMID 9703197.
  5. ^ Deakin, SP; James, RW (November 2004). "Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1". Clinical science (London, England : 1979). 107 (5): 435–47. PMID 15265000.
  6. ^ Harel M, Aharoni A, Gaidukov L, Brumshtein B, Khersonsky O, Meged R, Dvir H, Ravelli RB, McCarthy A, Toker L, Silman I, Sussman JL, Tawfik DS (2004). "Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes". Nat Struct Mol Biol. 11 (5): 412–9. doi:10.1038/nsmb767. PMID 15098021.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Costa LG, Cole TB, Vitalone A, Furlong CE (2005). "Measurement of paraoxonase (PON1) status as a potential biomarker of susceptibility to organophosphate toxicity". CLINICA CHEMICA ACTA. 352 (1–2): 37–47. doi:10.1016/j.cccn.2004.09.019. PMID 15653099.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Getz GS, Reardon CA (2005). "Paraoxonase, a cardioprotective enzyme: continuing issues". Curr. Opin. Lipidol. 15 (3): 261–7. doi:10.1097/00041433-200406000-00005. PMID 15166781.
  9. ^ Mackness M, Mackness B (2005). "Paraoxonase 1 and atherosclerosis: is the gene or the protein more important?". Free Radic. Biol. Med. 37 (9): 1317–23. doi:10.1016/j.freeradbiomed.2004.07.034. PMID 15454272.
  10. ^ Khateeb J, Gantman A, Kreitenberg AJ, Aviram M, Fuhrman B (January 2010). "Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway". Atherosclerosis. 208 (1): 119–25. doi:10.1016/j.atherosclerosis.2009.08.051. PMID 19783251.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Khersonsky, O; Tawfik, DS (26 April 2005). "Structure-reactivity studies of serum paraoxonase PON1 suggest that its native activity is lactonase". Biochemistry. 44 (16): 6371–82. PMID 15835926.
  12. ^ Clendenning, JB; Humbert, R; Green, ED; Wood, C; Traver, D; Furlong, CE (1 August 1996). "Structural organization of the human PON1 gene". Genomics. 35 (3): 586–9. PMID 8812495.
  13. ^ a b c Costa, LG; Vitalone, A; Cole, TB; Furlong, CE (15 February 2005). "Modulation of paraoxonase (PON1) activity". Biochemical pharmacology. 69 (4): 541–50. PMID 15670573.
  14. ^ a b c Schrader, C; Graeser, AC; Huebbe, P; Wagner, AE; Rimbach, G (February 2012). "Allyl isothiocyanate as a potential inducer of paraoxonase-1--studies in cultured hepatocytes and in mice". IUBMB life. 64 (2): 162–8. PMID 22131196.
  15. ^ a b La Du, B.N (1992). "Human serum paraoxonase/arylesterase". In Kalow, W (ed.). Pharmacogenetics of Drug Metabolism. New York: Pergamon Press. p. 51. {{cite book}}: More than one of |pages= and |page= specified (help)
  16. ^ McDaniel, CY; Dail, MB; Wills, RW; Chambers, HW; Chambers, JE (December 2014). "Paraoxonase 1 polymorphisms within a Mississippi USA population as possible biomarkers of enzyme activities associated with disease susceptibility". Biochemical genetics. 52 (11–12): 509–23. PMID 25027835.
  17. ^ Costa, LG; Giordano, G; Cole, TB; Marsillach, J; Furlong, CE (10 May 2013). "Paraoxonase 1 (PON1) as a genetic determinant of susceptibility to organophosphate toxicity". Toxicology. 307: 115–22. PMID 22884923.
  18. ^ Mackness, M; Mackness, B (2014). "Current aspects of paraoxonase-1 research". In Komoda, Tsugikazu (ed.). The HDL handbook : biological functions and clinical implications (Second edition. ed.). Amsterdam: Academic Press. ISBN 978-0-12-407867-3.
  19. ^ Costa, LG; Cole, TB; Jarvik, GP; Furlong, CE (2003). "Functional genomic of the paraoxonase (PON1) polymorphisms: effects on pesticide sensitivity, cardiovascular disease, and drug metabolism". Annual review of medicine. 54: 371–92. PMID 12525679.
  20. ^ Camps, J; Pujol, I; Ballester, F; Joven, J; Simó, JM (April 2011). "Paraoxonases as potential antibiofilm agents: their relationship with quorum-sensing signals in Gram-negative bacteria". Antimicrobial agents and chemotherapy. 55 (4): 1325–31. PMID 21199929.
  21. ^ Lee, YS; Park, CO; Noh, JY; Jin, S; Lee, NR; Noh, S; Lee, JH; Lee, KH (September 2012). "Knockdown of paraoxonase 1 expression influences the ageing of human dermal microvascular endothelial cells". Experimental dermatology. 21 (9): 682–7. PMID 22897574.
  22. ^ Huen K, Harley K, Bradman A, Eskenazi B, Holland N (April 2010). "Longitudinal changes in PON1 enzymatic activities in Mexican-American mothers and children with different genotypes and haplotypes". Toxicol. Appl. Pharmacol. 244 (2): 181–9. doi:10.1016/j.taap.2009.12.031. PMC 2846980. PMID 20045427.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ Wang J, Liu Z (Nov 2000). "No association between paraoxonase 1 (PON1) gene polymorphisms and susceptibility to Parkinson's disease in a Chinese population". Mov Disord. 15 (6): 1265–7. doi:10.1002/1531-8257(200011)15:6<1265::AID-MDS1034>3.0.CO;2-0. PMID 11104219.

Further reading

  • Furlong CE, Costa LG, Hassett C; et al. (1993). "Human and rabbit paraoxonases: purification, cloning, sequencing, mapping and role of polymorphism in organophosphate detoxification". Chem. Biol. Interact. 87 (1–3): 35–48. doi:10.1016/0009-2797(93)90023-R. PMID 8393745. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • Furlong CE, Cole TB, Jarvik GP, Costa LG (2002). "Pharmacogenomic considerations of the paraoxonase polymorphisms". Pharmacogenomics. 3 (3): 341–8. doi:10.1517/14622416.3.3.341. PMID 12052142.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Mackness B, Durrington PN, Mackness MI (2003). "The paraoxonase gene family and coronary heart disease". Curr. Opin. Lipidol. 13 (4): 357–62. doi:10.1097/00041433-200208000-00002. PMID 12151850.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Costa LG, Cole TB, Furlong CE (2003). "Polymorphisms of paraoxonase (PON1) and their significance in clinical toxicology of organophosphates". J. Toxicol. Clin. Toxicol. 41 (1): 37–45. doi:10.1081/CLT-120018269. PMID 12645966.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Furlong CE, Cole TB, Jarvik GP; et al. (2005). "Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants". Neurotoxicology. 26 (4): 651–9. doi:10.1016/j.neuro.2004.08.002. PMID 16112327. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
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