Association between CYP1A1 genotype, mRNA expression and enzymatic activity in humans.
Genetic susceptibility factors may play a role in determining adverse effects of exposure to environmental toxins. As a preliminary step to a molecular epidemiological study in a population exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD), we investigated 20 healthy Caucasian volunteers with a set of putative susceptibility markers including a CYP1A1 Msp I restriction fragment length genetic polymorphism (RFLP), CYP1A1 mRNA expression, and ethoxyresorufin-O-deethylase (EROD) activity in cultured and mitogen-activated blood lymphocytes. Both basal (p = 0.008) and induced (p = 0.0001) EROD activity was significantly higher among persons with a mutation in one or both alleles of the CYP1A1 gene (variant CYP1A1 genotype). Induction in vitro by TCDD significantly increased EROD activity in both variant and wild-type CYP1A1 subjects; however, the absolute increase was greater in subjects with variant genotypes. An additive interaction between genotype and TCDD induction was suggested. Expression of CYP1A1 mRNA, both basal and induced, did not vary significantly across the genotypes.
Landi
M T
MT
Genetic Epidemiology Branch, National Cancer Institute, Bethesda, MD 20892.
Bertazzi
P A
PA
Shields
P G
PG
Clark
G
G
Lucier
G W
GW
Garte
S J
SJ
Cosma
G
G
Caporaso
N E
NE
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D017931:DNA Primers; D004790:Enzyme Induction; D005260:Female; D005838:Genotype; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics*
D017931:DNA Primers; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1