4-n-Nonylphenol and bisphenol A are endocrine disrupting chemicals that are mainly detoxified through glucuronidation. A factor that may modulate their glucuronidation rates is co-exposure to pharmaceuticals.

This study aimed to identify and characterize the potential metabolic interactions between 14 drugs and these two endocrine disruptors. Nonylphenol and bisphenol A were co-incubated in freshly isolated rat hepatocytes with, drugs at a high concentration.

Statistically significant metabolic inhibition of bisphenol A and nonylphenol biotransformation was observed with nine drugs (>50% inhibition by naproxen, salicylic acid, carbamazepine and mefenamic acid). Inhibition assays of UGT activity in rat liver microsomes revealed: 1) competitive inhibition by naproxen (K(i)(app) = 848.3 muM) and carbamazepine (K(i)(app) = 1023.1 muM), 2) no inhibition by salicylic acid suggesting another mechanism of inhibition.

Detoxification of nonylphenol and bisphenol A was shown to be impaired by excessive concentrations of many drugs and health risk assessment should therefore address this issue.

Reference: Verner MA, Magher T, Haddad S., High concentrations of commonly used drugs can inhibit the in vitro glucuronidation of bisphenol A and nonylphenol in rats, Xenobiotica. 2009 Nov 16.

A recent paper on sauna therapy by Dr. Martin L. Pall argues for a novel mechanism for its mode of action (1). Pall argues that sauna therapy acts primarily by increasing the availability of a compound called tetrahydrobiopterin (BH4) in the body. BH4 is reported or thought to be depleted in a number of medical conditions that are also reported to respond positively to sauna therapy, including multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, hypertension, vascular endothelial dysfunction and heart failure. This pattern of action can be explained, therefore, if sauna therapy increases the availability in the body of BH4.

Pall argues for two distinct mechanisms by which sauna therapy is expected to increase availability of BH4. Both of these act by increasing the synthesis of an enzyme, known as GTP cyclohydolase I, the rate limiting enzyme in the biosynthesis of BH4.

Sauna therapy is known to produce large increases in blood flow in the outer heated parts of the body and the consequent increase in vascular shear stress has been shown to induce large increases in GTP cyclohydrolase I activity and consequent increases in BH4.

A second such mechanism is mediated through the action of the heat shock protein, Hsp90, a protein known to be induced by modest tissue heating and a protein that is recruited into a complex of proteins containing GTP cyclohydrolase I. The Hsp90 protein lowers the proteolytic degradation of GTP cyclohydrolase I protein, leading to increased BH4 synthesis and this has been shown to lower, in turn, the partial uncoupling of the eNOS nitric oxide synthase. Increases in BH4 synthesis in response to both of these two mechanisms may be expected to feed BH4 to various tissues in the body including those not directly impacted by sauna therapy.

The health benefits of vigorous exercise may also be mediated, in part, via these same mechanisms.

A number of additional diseases are reported to involved BH4 depletion including Alzheimer’s, Parkinson’s, asthma, schizophrenia, bipolar disorder, pulmonary hypertension and type 2 diabetes so that each of these may respond to sauna therapy, as well.

It has been commonly assumed that the response of MCS cases to sauna therapy is mediated by a detoxification process known as depuration. There is some published evidence that some increase in detoxification does occur in response to sauna therapy. However the main influence of sauna therapy on MCS cases and certainly in these other medical conditions may well be through increased BH4 availability.

Reference: 1. Pall ML. 2009 Do sauna therapy and exercise act by raising the availability of tetrahydrobiopterin? Med Hypotheses. 2009 Jul 4.

In a study with important consequences for studies on the effects of chemicals on steroid responses in humans, a team of French and American scientists, including Michael E. Baker, PhD, professor in UC San Diego’s Department of Medicine, Division of Nephrology-Hypertension, have found that – contrary to earlier assumptions – enzymes used for the synthesis of steroids in insects, snails, octopuses and corals are unrelated to those used in humans. 

The research, led by a team at the Université de Lyon, ENS Lyon, provides insight into the evolution of steroid hormone signaling and the relationship of steroid synthesis to enzymes that detoxify harmful chemicals in the environment. Their findings will be published the week of June 29, 2009 in the advance online publication of the Proceedings of the National Academy of Sciences (PNAS.) 

“The toxic effects of chemicals on snails and corals remain a major area of environmental concern,” said Vincent Laudet, professor in the Institute of Functional Genomics of Lyon, Division of Molecular Zoology. “For a long time, it has been thought that many invertebrate animals share with humans the same steroid hormones and enzymes that synthesize steroids. However, our research indicates that the method by which toxic chemicals effect the steroid hormone signaling of snails, corals, insects and other invertebrates can’t be extrapolated to human disease.” 

Steroids hormones are key to many vital physiological responses in humans, ranging from anti-inflammatory agents to regulating events during pregnancy. They are also the target of many chemical pollutants, known as endocrine disruptors. As part of a program to understand the evolution of steroid hormone signaling, Laudet – along with Gabriel Markov, a student in the Institute of Functional Genomics, initially trained by Raquel Tavares at Université de Lyon, characterized the evolutionary relationships between proteins that synthesize steroids in animals. They traced the origin of such enzymes from vertebrates, insects, snails and jelly fish and interpreted these results through extensive discussions with Baker, Chantal Dauphin-Villemant at Université Paris 6, and Barbara Demeneix from the National Museum of Natural History in Paris. 

Through an analysis of several invertebrate genomes, the scientists discovered that snails and insects utilize steroid-synthesizing enzymes that are not vertebrate–related, but instead belong in an invertebrate family. Moreover, these invertebrate steroidogenic enzymes have a strong evolutionary connection to enzymes that detoxify chemicals (called xenobiotics). 

This unexpected finding led them to hypothesize that these steroid-synthesizing enzymes arose independently from specific pathways used by snails and worms for detoxifying environmental chemicals. 

“This finding shows that, if we want to really understand the effects of environmental chemicals on steroid synthesis in snails, worms, octopuses and such animals, we must switch from a human-centered viewpoint to snail-centered viewpoint. This is the best way to accumulate knowledge that could be useful to human health,” said Laudet, adding that this emphasizes the need for more cross-disciplinary studies between toxicologists, endocrinologists and zoologists.  

Reference: University of California – San Diego, PR Toxic chemicals affect steroid hormones differently in humans and invertebrates, June 29, 2009