Polychlorinated biphenyl (PCB) induction of CYP3A4 enzyme activity in healthy Faroese adults

• Published in: Toxicology and applied pharmacology 2007-10, Vol.224 (2), p.202-206
• Main Authors: Petersen, Maria Skaalum, Halling, Jónrit, Damkier, Per, Nielsen, Flemming, Grandjean, Philippe, Weihe, Pál, Brøsen, Kim
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; 6β-Hydroxycortisol/cortisol ratio; Adolescent; Adult; Biological and medical sciences; CYP3A4; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - drug effects; Cytochrome P-450 Enzyme System - metabolism; DDT; DDT - blood; DDT - pharmacology; Dichlorodiphenyl Dichloroethylene - blood; Dichlorodiphenyl Dichloroethylene - pharmacology; Environmental Exposure; Environmental Pollutants - blood; Environmental Pollutants - pharmacology; ENZYME ACTIVITY; Enzyme Induction - drug effects; ENZYMES; ETHANE; ETHYLENE; Faroe Islands; Female; Genetics, Population; Humans; HYDROCORTISONE; Hydrocortisone - analogs & derivatives; Hydrocortisone - metabolism; Hydrocortisone - urine; Male; Medical sciences; METABOLISM; Middle Aged; Persistent organohalogen pollutants; POLLUTANTS; POLYCHLORINATED BIPHENYLS; Polychlorinated Biphenyls - blood; Polychlorinated Biphenyls - pharmacology; Polymorphism, Genetic; RECEPTORS; REGRESSION ANALYSIS; Sex Factors; Toxicogenetics; Toxicology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2007.07.002

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 6β-hydroxycortisol/cortisol (6β-OHC/FC) ratio. POP exposures were assessed by measuring their concentrations in serum lipid. The results showed a unimodal distribution of the 6β-OHC/FC ratio with values ranging from 0.58 to 27.38. Women had a slightly higher 6β-OHC/FC ratio than men ( p = 0.07). Confounder-adjusted multiple regression analysis showed significant associations between 6β-OHC/FC ratios and ∑PCB, PCB–TEQ and p, p′-DDE, o, p′-DDT and HCB, respectively, but the associations were statistically significant for men only.