Human CYP1A1 variants lead to differential eicosapentaenoic acid metabolite patterns.
To answer the question whether the most common allelic variants of human CYP1A1, namely CYP1A1.1 (wild type), CYP1A1.2 (Ile462Val), and CYP1A1.4 (Thr461Asn), differ in their catalytic activity towards eicosapentaenoic acid (EPA), in vitro enzymatic assays were performed in reconstituted CYP1A1 systems. All CYP1A1 variants catalyzed EPA epoxygenation and hydroxylation to 17(R),18(S)-epoxyeicosatetraenoic acid (17(R),18(S)-EETeTr) and 19-OH-EPA, yet with varying catalytic efficiency and distinct regiospecificity. CYP1A1.1 and CYP1A1.4 formed 17(R),18(S)-EETeTr as main product (K(m)=53 and 50 microM; V(max)=0.60 and 0.50 pmol/min/pmol; V(max)/K(m)=0.11 and 0.10 microM(-1)min(-1), respectively), followed by 19-OH-EPA (K(m)=76 and 93 microM; V(max)=0.37 and 0.37 pmol/min/pmol; V(max)/K(m)=0.005 and 0.004 microM(-1)min(-1), respectively). The variant CYP1A1.2 produced almost equal amounts of both metabolites, but its catalytic efficiency for hydroxylation was five times higher (K(m)=66 microM; V(max)=1.7 pmol/min/pmol; V(max)/K(m)=0.026 microM(-1)min(-1)) and that for epoxygenation was twice higher (K(m)=66 microM; V(max)=1.5 pmol/min/pmol; V(max)/K(m)=0.023 microM(-1)min(-1)) than those of the wild-type enzyme. Thus, the Ile462Val polymorphism in human CYP1A1 affects EPA metabolism and may contribute to interindividual variance in the local production of physiologically active fatty acid metabolites in the cardiovascular system and other extrahepatic tissues, where CYP1A1 is expressed or induced by polycyclic aromatic hydrocarbons and other xenobiotics.
Schwarz
Dieter
D
Institute of Clinical Pharmacology, Charité-Universitätsmedizin Berlin, Humboldt University of Berlin, 10098 Berlin, Germany. dieter.schwarz@charite.de
Kisselev
Pyotr
P
Chernogolov
Alexey
A
Schunck
Wolf-Hagen
WH
Roots
Ivar
I
D000483:Alleles; D019943:Amino Acid Substitution; D001095:Arachidonic Acids / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007700:Kinetics; D011110:Polymorphism, Genetic
D001095:Arachidonic Acids; D006893:Hydroxyeicosatetraenoic Acids; C070378:17,18-epoxy-5,8,11,14-eicosatetraenoic acid; C055986:19-hydroxy-5,8,11,14-eicosatetraenoic acid; D015118:Eicosapentaenoic Acid; D019363:Cytochrome P-450 CYP1A1