Variation in induced CYP1A1 levels: relationship to CYP1A1, Ah receptor and GSTM1 polymorphisms.
The genotypic basis of interindividual variation in levels of induced CYP1A1 activity has been investigated by screening both the CYP1A1 gene and the Ah receptor gene (AhR) for both previously described and novel polymorphisms. A 103-fold level of interindividual variation in induced CYPlA1 activity [ethoxyresorufin O-deethylase (EROD)] was observed in lymphocytes from a group of 30 Caucasian volunteers. High levels of induced EROD activity did not correlate with the presence of CYP1A1*2 or CYP1A1*4 alleles or with the GSTM1 null genotype. Novel CYP1A1 alleles with the base substitutions C4151T, G-469A and C-459T respectively, were detected by screening the coding exons and approximately 1 kb of upstream sequence in 20 individuals by single-strand conformational polymorphism (SSCP) analysis but none of the three novel alleles appeared to be associated with high induced CYP1A1 activity in the study group. Screening of the 11 exons of the AhR gene by SSCP analysis confirmed the existence of the previously described G1721A polymorphism in a Caucasian population and a novel allele (G1768A which results in the amino acid substitution V5701) was also detected. The novel allele was very rare in Caucasians though more common in African-Americans. Individuals with at least one copy of the G1721A AhR variant allele showed a significantly higher level of induced CYP1A1 activity compared with individuals negative for the polymorphism (P = 0.0001). A similar finding was obtained for induced CYP1A1 protein levels determined by immunoblotting. Levels of induced CYP1A1 activity were also found to show a sex difference with women showing a significantly lower induced activity compared with men. We conclude that genotypes for the G1721A AhR polymorphism and gender appear to be determinants of levels of induced CYP1A1 activity and that interindividual variation in levels of induced CYP1A1 activity appears to be associated more with regulatory factors than polymorphism in the CYP1A1 gene.
Smart
J
J
Department of Pharmacological Sciences, University of Newcastle upon Tyne, UK.
Daly
A K
AK
D000328:Adult; D000483:Alleles; D044383:Black People / Q000235:genetics; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism*; D004790:Enzyme Induction / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D010078:Oxazines / Q000378:metabolism; D017354:Point Mutation; D011110:Polymorphism, Genetic / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D012016:Reference Values; D044465:White People / Q000235:genetics; D001741:Black or African American
D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; D007527:Isoenzymes; D010078:Oxazines; D018336:Receptors, Aryl Hydrocarbon; C007649:ethoxyresorufin