Influences of Dietary and Other Factors on Xenobiotic Metabolism and Carcinogenesis-A Review Article in Memory of Dr. Allan H. Conney (1930-2013).

This article reviews our current understanding on how xenobiotic metabolism and carcinogenesis are influenced by dietary and other factors. A major contributor to this research area was Dr. Allan Conney, and his contributions are highlighted. His studies on the induction of microsomal xenobiotic-metabolizing enzymes led to the characterization of the cytochrome P450 enzymes, which catalyze the metabolism of drugs, endogenous substrates, carcinogens and many other xenobiotics. These processes are influenced by drugs, diet, and other environmental factors. These studies provided the molecular basis for drug-drug, diet-drug, and herb-drug interactions. The elucidation of the metabolic activation of chemicals to their ultimate carcinogenic forms enables us to understand the molecular basis of chemical carcinogenesis. These studies led to many subsequent investigations on dietary approaches for cancer chemoprevention, including blocking of carcinogen activation, enhancing carcinogen detoxification, and influencing oncogenic pathways, which were carried out by Dr. Conney and others. The strengths and potential for practical application of these approaches are assessed herein.

Forging the links between metabolism and carcinogenesis.

Metabolism plays important roles in chemical carcinogenesis, both good and bad. The process of carcinogen metabolism was first recognized in the first half of the twentieth century and developed extensively in the latter half. The activation of chemicals to reactive electrophiles that become covalently bound to DNA and protein was demonstrated by Miller and Miller [Cancer 47 (1981) 2327]. Today many of the DNA adducts formed by chemical carcinogens are known, and extensive information is available about pathways leading to the electrophilic intermediates. Some concepts about the stability and reactivity of electrophiles derived from carcinogens have changed over the years. Early work in the field demonstrated the ability of chemicals to modulate the metabolism of carcinogens, a phenomenon now described as enzyme induction. The cytochrome P450 enzymes play a prominent role in the metabolism of carcinogens, both in bioactivation and detoxication. The conjugating enzymes can also play both beneficial and detrimental roles. As an example of a case in which several enzymes affect the metabolism and carcinogenicity of a chemical, aflatoxin B1 (AFB1) research has revealed insight into the myriad of reaction chemistry that can occur even with a 1s half-life for a reactive electrophile. Further areas of investigation involve the consequences of enzyme variability in humans and include areas such as genomics, epidemiology, and chemoprevention.

Forty years of cytochrome P450.

The term "cytochrome P450" first appeared in literature in 1962. It was a microsomal membrane-bound hemoprotein without known physiological functions at that time and was characterized by a unique 450-nm optical absorption peak of its carbon monoxide-bound form, which was originally reported as the spectrum of a novel "microsomal carbon monoxide-binding pigment" in 1958. Elucidation of its function as the oxygenase in 1963 triggered a rapid expansion of research on this hemoprotein. Annual numbers of the published papers dealing with cytochrome P450, which were listed in Biological Abstracts, increased from 60 in 1970 to 500 in 1980, 900 in 1990, and 1500 in 1997. Cytochrome P450 is now regarded as the collective name of a large family of hemoproteins, "cytochrome P450 superfamily, "which seems to have diversified from a single ancestral protein to many forms during the course of biological evolution and is distributed widely among various forms of life from animals and plants to fungi and bacteria. Multicellular eukaryotic organisms including animals and plants have about 100 or more P450 genes in their genomes, and those many P450 genes are expressed tissue specifically and developmental stage specifically, indicating their diverse physiological functions. In mammals, various P450s participate in the biosynthesis and metabolism of sterols and steroid hormones and the metabolism of various lipid biofactors including eicosanoids, vitamin D3, and retinoids. Oxidative metabolism of foreign hydrophobic compounds as the first step of their excretion from the animal body is apparently another major function of cytochrome P450, which protects animals from noxious foreign compounds, man-created and natural.

Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998)--a review.

Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic effects of ethanol but does not account for the tolerance and a number of associated disorders that develop in the alcoholic. These were elucidated by the discovery of the microsomal metabolism of ethanol. The physiologic role of this system comprises gluconeogenesis from ketones, fatty acid metabolism, and detoxification of xenobiotics, including ethanol. After chronic ethanol consumption, the activity of the microsomal ethanol-oxidizing system (MEOS) increases, with an associated rise in cytochromes P-450, especially CYP2E1. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans. The role of MEOS in vivo and its increase after chronic ethanol consumption was shown most conclusively in alcohol dehydrogenase-negative deer mice. Enhanced ethanol oxidation is associated with cross-induction of the metabolism of other drugs, resulting in drug tolerance. Furthermore, there is increased conversion of known hepatotoxic agents (such as CCl4) to toxic metabolites, which may explain the enhanced susceptibility of alcoholics to the adverse effects of industrial solvents. CYP2E1 also has a high capacity to activate some commonly used drugs, such as acetaminophen, to their toxic metabolites, and to promote carcinogenesis (e.g., from dimethylnitrosamine). Moreover, catabolism of retinol is accelerated and there also is induction of microsomal enzymes involved in lipoprotein production, resulting in hyperlipemia. Contrasting with the chronic effects of ethanol consumption, acute ethanol intake inhibits the metabolism of other drugs through competition for the at least partially shared microsomal pathway. In addition, metabolism by CYP2E1 results in a significant free radical release and acetaldehyde production which, in turn, diminish reduced glutathione (GSH) and other defense systems against oxidative stress. Acetaldehyde also forms adducts with proteins, thereby altering the functions of mitochondria and of repair enzymes. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the area of maximal liver damage. CYP1A2 and CYP3A4, two other perivenular P-450s, can also sustain the metabolism of ethanol, thereby contributing to MEOS activity and possibly liver injury. By contrast, CYP2E1 inhibitors oppose alcohol-induced liver damage, but heretofore available compounds were too toxic for clinical use. Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of polyunsaturated lecithins extracted from soybeans, was discovered to decrease CYP2E1 activity. PPC (and its active component dilinoleoylphosphatidylcholine) also oppose hepatic oxidative stress and fibrosis. PPC is now being tested clinically for the prevention and treatment of liver disease in the alcoholic.