Polychlorinated biphenyl (PCB) induction of CYP3A4 enzyme activity in healthy Faroese adults.
The CYP3A4 enzyme is, along with other cytochrome P450 enzymes, involved in the metabolism of environmental pollutants and is highly inducible by these substances. A commercial polychlorinated biphenyl (PCB) mixture, 1,1,1,-trichloro-2-(o-chlorophenyl), 2-(p'-chlorophenyl)ethane (o,p'-DDT) and 1,1,-dichloro-2,2-bis (p-chlorophenyl)ethene (p,p'-DDE) are known to induce CYP3A4 activity through activation of nuclear receptors, such as the pregnane X receptor. However, this induction of CYP3A4 has not yet been investigated in humans. Thus, the aim of the study was to determine the variability of the CYP3A4 phenotype in regard to increased concentrations of PCBs and other persistent organohalogen pollutants (POPs) in healthy Faroese adults. In 310 randomly selected Faroese residents aged 18-60 years, the CYP3A4 activity was determined based on the urinary 6beta-hydroxycortisol/cortisol (6beta-OHC/FC) ratio. POP exposures were assessed by measuring their concentrations in serum lipid. The results showed a unimodal distribution of the 6beta-OHC/FC ratio with values ranging from 0.58 to 27.38. Women had a slightly higher 6beta-OHC/FC ratio than men (p=0.07). Confounder-adjusted multiple regression analysis showed significant associations between 6beta-OHC/FC ratios and summation PCB, PCB-TEQ and p,p'-DDE, o,p'-DDT and HCB, respectively, but the associations were statistically significant for men only.
Petersen
Maria Skaalum
MS
Institute of Public Health, Environmental Medicine, University of Southern Denmark, Winsløvparken 17, 5000 Odense C, Denmark. mskaalum@health.sdu.dk
Halling
Jónrit
J
Damkier
Per
P
Nielsen
Flemming
F
Grandjean
Philippe
P
Weihe
Pál
P
Brøsen
Kim
K
D000293:Adolescent; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D003634:DDT / Q000097:blood / Q000494:pharmacology; D003633:Dichlorodiphenyl Dichloroethylene / Q000097:blood / Q000494:pharmacology; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000097:blood / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects*; D005260:Female; D005828:Genetics, Population; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D008297:Male; D008875:Middle Aged; D011078:Polychlorinated Biphenyls / Q000097:blood / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D012737:Sex Factors; D043922:Toxicogenetics
D004785:Environmental Pollutants; D003633:Dichlorodiphenyl Dichloroethylene; C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; D003634:DDT; C016340:o,p'-DDT; D011078:Polychlorinated Biphenyls; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006854:Hydrocortisone