The association between chemical-induced porphyria and hepatic cancer

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.

Porphyria cutanea tarda increases risk of hepatocellular carcinoma and premature death: a nationwide cohort study

“…It has been proposed that the accumulation of uroporpohyrins, of which levels are high in (untreated) PCT, may cause liver injury, resulting in the formation of a hepatic tumor [27]. This may occur in parallel or by interaction with exposure to hepatotoxic factors, such as alcohol.…”

Researches on the evaluation of pesticide safety in humans using a pharmacokinetic approach

“…Thus, it is believed that PPO inhibitors can cause toxicity especially in PPO-generating organs such as the liver and can occasionally induce hepatocellular tumors as a consequence of hepatotoxicity. 11,12) Also, PPO catalyzes the oxidation of protoporphyrinogen IX to PPIX during heme biosynthesis in both plants and mammals. In mammals, the inhibition of PPO blocks the production of hemoglobin and erythrocytes, resulting in anemia.…”

Models for human porphyrias: Have animals in the wild been overlooked?

“…[ 52–54 ] It is believed that porphyrin accumulation is the carcinogenic agent in porphyrias, but the molecular mechanisms are still not fully understood. [ 55 ]…”

“…[52][53][54] It is believed that porphyrin accumulation is the carcinogenic agent in porphyrias, but the molecular mechanisms are still not fully understood. [55] Most importantly, the Harderian gland of rodents is both a site of production and a site of storage of porphyrins, leading to accumulations that in some species exceed 2000 nmol porphyrin/g tissue. [47] Despite these accumulated amounts of porphyrins and an activity of enzymes such as ALA synthase that in the golden hamster is up to 100 times higher than in other organs, and even after an experimental ca.…”