Analysis of human Polychlorinated biphenyls(PCB)-metabolism in order to predict individual risk to disease

Status:

completed 07/2023

Aims:

The main aim of this project was to identify certain enzymes, known as cytochrome P450 monooxygenases (CYP enzymes), which contribute to the formation of harmful metabolites from certain types of polychlorinated biphenyls (PCBs). PCBs are chemicals that, when metabolically activated, can increase their toxicity and mutagenicity, meaning they can potentially cause damage to our DNA and increase the risk of genetic mutations. However, we still do not know exactly how this metabolic activation occurs in the human body, particularly in the liver. This lack of knowledge makes it difficult to accurately assess the potential risks and effects of these chemicals. This project aimed to close these knowledge gaps and improve our understanding of these processes. The results could help to improve the assessment of people who have been exposed to these chemicals at work and who are suspected of having an occupational disease. They could also help to identify high-risk groups who could benefit from preventive occupational health measures. In simpler terms, this project was about understanding how PCB congeners 28, 52, 101 and 118 are processed in our bodies, particularly in the liver, and whether this can amplify their harmful effects. Knowing this can help us to better assess and manage the health risks associated with exposure to these chemicals.

Activities/Methods:

The project was divided into two parts:

• Firstly, the CYP enzymes responsible for the degradation of PCB congeners 28, 52, 101 and 118 were identified.
• Secondly, an in vitro system was developed that can predict whether the metabolisation of these PCBs can cause cell damage or genetic changes.

Results:

Experiments have shown that the enzymes CYP1A2 and CYP2A6 play an important role in the metabolisation of PCB congeners 28, 52 and 101. The enzyme CYP2E1 was identified for the metabolisation of PCB 118. It was also shown that both PCB 28 and PCB 101 cause genetic changes and cell damage in vitro. Metabolisation of PCB 28 by the enzymes CYP1A2 and CYP2A6 can produce the compound 3-OHCB15 through a process known as dechlorination. This compound can be further converted into other compounds, so-called hydroquinones, which have been shown to trigger the development of tumours in animal experiments. As part of the project, 3-OHCB15 was detected in higher concentrations in blood samples from people in the HELPcb cohort.

In an independently from FB295 conducted pharmacological study, the metabolic activity of CYP2A6 was investigated in individuals from the HELPcB cohort. One person was identified with a significantly increased activity of CYP2A6 with regard to the metabolisation of paraxanthine. Retrospectively, an increased metabolism of PCB28 was detected in the same person. This result confirmed the outstanding importance of the enzyme CYP2A6 identified by us for the metabolism of the World Health Organization (WHO) indicator congener PCB 28 in vivo and indicates that CYP2A6 plays an important role in the metabolisation of PCB 28 in the human body.

In practical application, the metabolism of PCB28 to hydroxylated PCB 15 (3-OHCB15) and the resulting hydroquinone metabolite should be taken into account when assessing the risk potential of PCB mixtures. The formation and elimination of the carcinogenic metabolite of PCB 28, 3-OHPCB15, is dependent on the enzymes CYP1A2 and CYP2A6, for which genetic variations exist in the population that increase their activity. Employees occupationally exposed to PCB 28 with an increased activity of these enzymes probably show an increased genotoxic effect of PCB 28.

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