Phenylalanine 4-monooxygenase and the role of endobiotic metabolism enzymes in xenobiotic biotransformation.
Phenylalanine 4-monooxygenase is the key enzyme in the sulfoxidation of the thioether drug S-carboxymethyl-l-cysteine and its thioether metabolites, S-methyl-l-cysteine, N-acetyl-S-carboxymethyl-l-cysteine and N-acetyl-S-methyl-l-cysteine in humans, and a number of other mammalian species. The kinetics constants of the sulfoxidation reaction (K(m), V(max) and CL(E)) have been investigated in cytosolic fractions derived from rat and human liver, in cytosolic fractions of HepG2 cells and using both human and mouse cDNA expressed phenylalanine 4-monooxygenase. Differences in K(m), V(max) and CL(E) of S-carboxymethyl-l-cysteine have been seen in HepG2 cells and human and mouse cDNA expressed phenylalanine 4-monooxygenase when compared to both rat and human hepatic cytosolic fractions. The association of the genetic polymorphism in the sulfoxidation of S-carboxymethyl-l-cysteine is highlighted with particular reference to this biotransformation reaction as being a biomarker of disease susceptibility in Parkinson's, Alzheimer's and motor neurone diseases and in rheumatoid arthritis. The possible underlying molecular genetics of the sulfoxidation polymorphism is also discussed in relation to the known allelic frequencies of phenylalanine 4-monooxygenase. Finally, the new found role phenylalanine 4-monooxygenase plays in xenobiotic metabolism is discussed.
Steventon
Glyn B
GB
King's College London, School of Biomedical and Health Sciences, Pharmaceutical Science Division, Franklin Wilkins Building, 150 Stamford Street, London SE1 9NH, UK. glyn.steventon@kcl.ac.uk
Mitchell
Stephen C
SC
D000483:Alleles; D000818:Animals; D002233:Carbocysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D010651:Phenylalanine Hydroxylase / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D051381:Rats; D013454:Sulfoxides / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism*
D013454:Sulfoxides; D015262:Xenobiotics; C018243:S-(2-carboxyethyl)cysteine; D002233:Carbocysteine; D010651:Phenylalanine Hydroxylase