Cytochrome P450Mediated Effects

The mechanism of action for dioxin and dioxin-like compounds is generally accepted to function through binding to a specific protein in the cytoplasm of cells, the aryl hydrocarbon receptor (AhR). Once bound, the dioxin/AhR complex can bind to DNA in the cell nucleus, which results in the increased production of several proteins, particularly in the production of cytochrome P450 1A1. The binding of dioxins to the AhR is the essential step for the expression of dioxin-related effects in vertebrate species. Induction of this

Table 2 Six main types of effects commonly ascribed to dioxins and dioxin-like compounds

Possible effect

Current knowledge

Cytochrome P450 induction

Immune system suppression

Porphyria

Cancer promotion

Disruption of vitamin A

metabolism Sex hormone effects

It is believed that the root cause of many of the effects of dioxins lies in their ability to bind to a specific protein in the cytoplasm of body cells, the aryl hydrocarbon (Ah) receptor. This leads to the synthesis of P450-dependent enzymes, which, in turn, can affect the metabolism of useful substances like steroid hormones, leading to disturbances in critical biological functions

Dioxins are widely held to have effects on the immune systems of exposed animals. It is suspected that this type of effect contributed to the mass mortalities of seals and dolphins in European waters in the late 1980s and early 1990s. The mechanism for immune system effects is not well understood

Hepatic porphyria is a condition in which there is disruption of the process by which the liver produces a component of the blood pigment hemoglobin. Dioxins are known to disrupt the process leading to sensory disorders, paralysis, and psychological effects

An association between dioxins and cancer has been recognized for some time, TCDD causing skin and liver tumors in mice at lower concentrations than any other substance. It is felt by some authorities that dioxins are not mutagenic (i.e., do not initiate cancer development), but it is generally felt that they are strong promoters of tumor development

Dioxins can inhibit the process by which vitamin A is stored in the liver. Decreased vitamin A storage, and increased levels in the blood, can result in fetal damage, growth disorders, and sterility

Dioxins have been found to have significant effects on the sex hormones estrogen and testosterone. In rats, this has been found to result in decreased fertility and increased incidence of tumors in females and low testosterone levels in males protein translates into an increased production of enzymes capable of oxidizing both foreign and endogenous substances. Although the function of this response may be to protect the cell from potential damage, cytochrome P450 induction can affect metabolism of endogenous substances like steroid hormones, leading to disturbances in critical biological functions. Taxonomic groups that possess the AhR such as fish, birds, and mammals show far greater susceptibility to dioxins than plants and most invertebrates, which generally do not possess this receptor.

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