Detoxication of carcinogenic fjord-region diol epoxides of polycyclic aromatic hydrocarbons by glutathione transferase P1-1 variants and glutathione.
Epidemiological studies suggest that individuals differing in the expression of allelic variants of the human glutathione transferase (GST) Pi gene differ in susceptibility to chemical carcinogens such as polycyclic aromatic hydrocarbons (PAH). This study reports the catalytic efficiencies (k(cat)/Km) of two naturally occurring variants, GSTP1-1/I-105 and GSTP1-1/ V-105, towards a series of fjord-region diol epoxides representing potent biologically active PAH metabolites, and two GSTP1-1 mutants with Ala105 and Trp105 in the active site. The results indicate that individuals who are homozygous for the allele encoding GSTP1-1/V-105 might be more susceptible to PAH carcinogenesis due to other reasons than a reduced capacity for detoxifying diol epoxides.
Sundberg
K
K
Institute of Environmental Medicine, Division of Biochemical Toxicology, Karolinska Institutet, Stockholm, Sweden.
Seidel
A
A
Mannervik
B
B
Jernström
B
B
D002273:Carcinogens / Q000737:chemistry / Q000493:pharmacokinetics*; D002384:Catalysis; D014644:Genetic Variation; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D007700:Kinetics; D015394:Molecular Structure; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry* / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship
D002273:Carcinogens; D011084:Polycyclic Aromatic Hydrocarbons; D005982:Glutathione Transferase; D005978:Glutathione