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Arthur Cederbaum, Ph.D.

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SW: Please expand on the importance of the liver enzyme called CYP2E1.

AC: Cytochrome P450s are present in many tissues but the highest levels are found in the liver. These enzymes help our bodies remove exogenous compounds present in our foods and environment, and promote detoxification processes such as removing drugs and other foreign agents. While cytochrome P450s usually help remove foreign compounds from our bodies via non-toxic reactions, some cytochrome P450s – such as CYP2E1 – can actually activate these compounds into becoming more toxic, reactive products. Furthermore, the liver enzyme CYP2E1 be induced and elevated by alcohol.

In addition, although alcohol dehydrogenase is the major enzyme system for oxidizing alcohol, CYP2E1 can also metabolize alcohol after chronic alcohol treatment. CYP2E1 is of special toxicological interest since it may produce reactive oxygen species (ROS) (http://184.107.204.92/node/121 ).

SW: Please expand on the dangers of reactive oxygen species (ROS).

AC: ROS, as the name implies, are very reactive as they react and inactivate all cellular macromolecules: they inactivate enzymes and denature proteins, damage cell membranes by oxidizing the lipids which hold membranes together, and hydrolyze RNA and DNA leading to mutations and carcinogenesis. ROS have been implicated in many diseases cederbaum quoteincluding inflammation, drug toxicity, iron toxicity, radiation injury, atherosclerosis, stroke, neurodegenerative diseases, asbestos and smoke injury,
metal toxicity, aging, and others.

Our laboratory set out 30 years
ago to evaluate the possible role
of ROS in alcohol-induced liver injury. Our general hypothesis
was that chronic alcohol intake induced CYP2E1 and that this increase resulted in an increase in ROS production, followed by liver damage.

Over the years, we showed that relative to other P450s, CYP2E1 was indeed especially effective in generating ROS. Systems in which alcohol induced CYP2E1, also displayed elevated ROS production followed by liver injury. Fortunately, liver injury could be blunted by inhibitors of CYP2E1, and by antioxidants such as vitamins E or C, which removed the ROS.

Our rodent research was especially helpful. In vivo, acute or chronic alcohol administration elevated hepatic levels of CYP2E1 and caused fatty liver, the hallmark of alcohol-induced liver injury in wild type mice but not in CYP2E1 knockout mice. Thus we learned that alcohol-induced fatty liver, and ROS production, require CYP2E1. When we restored CYP2E1 in the CYP2E1 knockout mice, we restored ROS production, fatty liver and liver injury, thus proving that the lack of effects of alcohol in the CYP2E1 knockout mice were due to the absence of CYP2E1 and not secondary effects.

SW: How does your research have an impact on people's day-to-day lives?

AC: We believe our studies have implicated CYP2E1 and the production of ROS as a major mechanism by which alcohol damages the liver. Consequently, it is possible that alcohol cederbaum quote2fatty liver, oxidant stress, and liver injury may be attenuated by inhibition of CYP2E. We are currently evaluating new inhibitors of CYP2E1 that are not toxic. We, and others, are evaluating the ability of antioxidants to blunt alcohol toxic effects to the liver. We are especially interested in developing activators of Nrf2 – a master transcription factor – which increase expression of several liver antioxidant genes at once. The underlying idea is that elevating several antioxidants at one time might be much more effective than administering one antioxidant at a time.

While our studies have focused on the liver, CYP2E1 is also present in other tissues, such as the pancreas and brain, which are damaged by alcohol. It is possible that alcohol induction of CYP2E1 and the subsequent elevation in oxidant stress may play a role in alcohol toxicity to other tissues than just the liver. There is much current interest in the role of oxidant stress in neurodegenerative diseases, pancreatitis, myocardial effects of alcohol, metabolic syndrome. Perhaps our studies with liver CYP2E1 and ROS may have implications for non-hepatic actions of alcohol.

SW: What have you been grateful for during your long career?

AC: Throughout this journey, I have been most fortunate in having outstanding, bright, and motivated graduate students and postdoctoral fellows in the lab — the foot soldiers who did the actual work. I am especially proud that many of these researchers have gone on to their own careers as independent investigators, several continuing to study CYP2E1 and alcohol-induced oxidant stress. Our laboratory has been generously supported for close to 40 years by the National Institute on Alcohol Abuse and Alcoholism and we have had much help, advice, and guidance by Institute officials. Excellent suggestions and clarifications have been made by anonymous reviewers of our grants and publications, many of whom have became colleagues and friends. I have had the honor of serving and chairing Biomedical Study Sections and being on the Editorial Boards of several journals where I learned a great deal on how to write a grant or an article and where I tried to give back and help.

SW: What does the RSA Lifetime Achievement Award mean to you?

AC: I believe this is the most meaningful award to me personally. I joined RSA in 1977 as an original member, had a publication in the very first issue of Alcoholism: Clinical Experimental Research, have published original papers, reviews and symposia in ACER, and served as an Associate Editor under Dr. Marcus Rothschild for many years. Most of my scientific colleagues are members of RSA and I have learned much at RSA meetings, not only in my own specific areas of interest but also in other areas where I generally do not follow the primary literature. This Award, I will always cherish.

More information about Dr. Cederbaum is availible on the Mount Sinai Hospital website: http://www.mountsinai.org/profiles/arthur-i-cederbaum


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