The intracellular concentration of free unbound acyl-CoA esters is tightly controlled by feedback inhibition of the acyl-CoA synthetase and is buffered by specific acyl-CoA binding proteins. Excessive increases in the concentration are expected to be prevented by conversion into acylcarnitines or by hydrolysis by acyl-CoA hydrolases. Under normal physiological conditions the free cytosolic concentration of acyl-CoA esters will be in the low nanomolar range, and it is unlikely to exceed 200 nM under the most extreme conditions. The fact that acetyl-CoA carboxylase is active during fatty acid synthesis (Ki for acyl-CoA is 5 nM) indicates strongly that the free cytosolic acyl-CoA concentration is below 5 nM under these conditions. Only a limited number of the reported experiments on the effects of acyl-CoA on cellular functions and enzymes have been carried out at low physiological concentrations in the presence of the appropriate acyl-CoA-buffering binding proteins. Re-evaluation of many of the reported effects is therefore urgently required. However, the observations that the ryanodine-senstitive Ca2+-release channel is regulated by long-chain acyl-CoA esters in the presence of a molar excess of acyl-CoA binding protein and that acetyl-CoA carboxylase, the AMP kinase kinase and the Escherichia coli transcription factor FadR are affected by low nanomolar concentrations of acyl-CoA indicate that long-chain acyl-CoA esters can act as regulatory molecules in vivo. This view is further supported by the observation that fatty acids do not repress expression of acetyl-CoA carboxylase or Delta9-desaturase in yeast deficient in acyl-CoA synthetase.

Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling.

Coenzyme A: back in action.

Gut microbiome interactions with drug metabolism, efficacy, and toxicity.

The literature was reviewed to obtain data from 11 mammalian species on liver weight, hepatic blood flow, and antipyrine intrinsic clearance. It was demonstrated that liver weight and hepatic blood flow in all species could be readily related to body weight by a simple equation. Additionally, hepatic blood flow in all species was directly proportional to liver weight. With the exception of man, antipyrine intrinsic clearance was also directly proportional to liver weight. Man's intrinsic clearance was approximately one-seventh of that which would be predicted from other species. Data on benzodiazepines and phenytoin showed a similar pattern.

Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: Extrapolation of data to benzodiazepines and phenytoin

In this review we have evaluated the relationship between peroxisome proliferation and hepatocarcinogenesis. To do so, we identified all chemicals known to produce peroxisome proliferation and selected those for which there are data (on peroxisome proliferation and hepatocarcinogenesis) which meet certain criteria chosen to facilitate comparison of these phenomena. The summarised data and definition of the methodology used has been collected in appendices. These comparisons enabled us to evaluate the relationship between these phenomena using reliable data. As there is a good correlation between them, we further explored the mechanisms of action that have been proposed (direct genotoxic activity, production of hydrogen peroxide, cell proliferation and receptor activation). The relationship between these events in other species, including humans, was also reviewed and finally an overview of the assessment of human hazard is presented in section IX. Some of the first chemicals which were shown to produce peroxisome proliferation were also hepatocarcinogens whose carcinogenicity could not be readily explained by genotoxic activity. This raised the suggestion that the unusual phenomenon of peroxisome proliferation was intricately linked to the carcinogenic activity of these agents. Three questions have exercised the attention of regulatory, industrial and academic toxicology since then; are chemicals which elicit peroxisome proliferation in the liver actually a coherent class of chemical carcinogens?; does the early biological phenomenon of peroxisome proliferation have real predictive value for and mechanistic association with rodent carcinogenesis?; and what hazard/risk do these agents pose to humans that may be exposed to them? Whether peroxisome proliferators are indeed a discrete class of rodent carcinogens would appear to be the single, most important question. If so, then the assumptions and procedures relevant to human hazard and risk assessment should be applied to the class and should be essentially generic; if not, each chemical should be considered independently. Our critical analysis of the published data for over 70 agents which have been shown to possess intrinsic ability to induce peroxisome proliferation in the livers of rodents has led to the conclusion that there exists a strong correlation between peroxisome proliferation as n early effect in the liver and hepatocarcinogenicity in chronic exposure studies. An almost perfect correlation was observed between the induction of peroxisomes in the rodent liver and the eventual appearance of tumours following chronic exposure The few exceptions to this were largely explainable (section II).(ABSTRACT TRUNCATED AT 400 WORDS)

Olav M. Bakke

Papers

Hydroxylation of aromatic hydrocarbons in the rat

Changes in lipid metabolizing enzymes of hepatic subcellular fractions from rats treated with tiadenol and clofibrate

Hepatic enzymes, CoASH and long-chain acyl-CoA in subcellular fractions as affected by drugs inducing peroxisomes and smooth endoplasmic reticulum.

Urinary simple phenols in rats fed diets containing different amounts of casein and 10 per cent tyrosine.

Urinary Simple Phenols in Rats Fed Purified and Nonpurified Diets