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|Title:||The association between chemical-induced porphyria and hepatic cancer|
|Authors:||Smith, Andrew G.|
Foster, John R.
|Publisher:||Royal Society of Chemistry|
|Citation:||Toxicology Research, 2018, 7, pp. 647–663|
|Abstract:||The haem biosynthetic pathway is of fundamental importance for cellular metabolism both for the erythroid and nonerythroid tissues. There are several genetic variants of the pathway in the human population that cause dysfunction of one or other of the enzymes resulting in porphyrias of varying severity. Serious chronic hepatic and systemic diseases may result. Some of these can be precipitated by exposure to drugs including hormones, barbiturates and antibiotics, as well as alcohol and particular chlorinated aromatic chemicals. In experimental animals some of the steps of this pathway can also be severely disrupted by a variety of environmental chemicals, potential drugs and pesticides, especially in the liver, leading to the accumulation of uroporphyrins derived from the intermediate uroporphyrinogens or protoporphyrin IX, the immediate precursor of haem. With some of these chemicals this also leads to cholestasis and liver cell injury and eventually hepatic tumours. The review evaluates the available evidence linking hepatic porphyria with carcinogenesis in naturally occurring human genetic conditions and in chemically-induced porphyrias in laboratory animals. The existing data showing gender, strain, and species differences in sensitivity to the chemical-induced porphyrias, liver injury and liver tumours are discussed and the role that transgenically altered mouse models have played in defining the varying mechanisms. Finally, the review proposes a novel, unifying hypothesis linking the hepatotoxicity induced by the accumulation of various porphyrins, with the increased risk of developing hepatic cancer as a long term consequence.|
|Rights:||Copyright © the authors, 2018. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-commercial License (https://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted use, distribution, and reproduction in any medium non-commercially, provided the original author and source are credited.|
|Description:||Preliminary presentation on this topic took place to a HESI Workshop U.S. EPA, 2004.|
|Appears in Collections:||Published Articles, MRC Toxicology Unit|
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