Two major forms of hepatic microsomal cytochrome P-450 were purified from starved and acetone-treated rats. On the basis of amino acid sequence analysis, they were identified as P-450j and P-450b. Ethanol or acetone treatment of rats caused a 9-fold increase in the amount of P-450j in liver microsomes accompanied by similar increases in the rate of NADPH-dependent metabolism of carbon tetrachloride, acetone, and benzene. Immunological experiments indicated that P-450j constitutes the major catalyst of the microsomal metabolism of the latter agents and contributes by about 50% to microsomal P-450-dependent ethanol oxidation under the conditions used. The P-450j-dependent catalytic activities had a high rate of turnover. In contrast, this was not the case for the immunodetectable P-450j, indicating the occurrence of inactive forms of this protein in microsomes. Starvation or ethanol or acetone treatment caused 10-30-fold increases in the amount of both mRNA and apoprotein of P-450b,e compared to control. Run-on experiments and the concomitant increases of the P-450b,e gene products at the mRNA and protein levels indicated the appearance of mainly a transcriptional activation by acetone, ethanol, or starvation. Fasting exerted, in addition, a pronounced synergistic effect on acetone-dependent induction of P-450b,e mRNA (3-fold), apo-P-450b,e (4.3-fold), P-450j mRNA (2-fold), and apo-P-450j (2-fold). No increase of mRNA coding for P-450j, compared to control, was seen after acetone or ethanol treatment alone. The results indicate that effects of ethanol, acetone, and/or starvation on drug and xenobiotic metabolism are caused by the induction of P-450 forms belonging to at least two gene subfamilies.

Ethanol-, fasting-, and acetone-inducible cytochromes P-450 in rat liver: regulation and characteristics of enzymes belonging to the IIB and IIE gene subfamilies.

Numerous halogenated hydrocarbons of the alkane, alkene, and alkyne classes are metabolized by P450 enzymes to products that elicit cytotoxic and/or carcinogenic effects. Such halogenated hydrocarbons include anesthetics (e.g., halothane and enflurane) and industrial solvents (e.g., carbon tetrachloride, chloroform, and vinylidine chloride). Formation of reaction intermediates from these compounds occurs via P450-promoted dehalogenation, reduction, or reductive oxygenation, with certain hydrocarbons undergoing all three reaction types. Of the multiple forms of P450 present in liver microsomes, P4502E1 has been identified as the primary catalyst of hydrocarbon bioactivation in animals and, most likely, in humans as well. As hepatic concentrations of this P450 enzyme are highly inducible by ethanol and similar agents, prior exposure to 2E1-inducing compounds can play a pivotal role in halogenated hydrocarbon toxicity. Considering that metabolism governs the cytotoxicity and carcinogenicity of halogenated hydrocarbons, an understanding of the mechanism(s) underlying 2E1 induction in man becomes all the more important.

Bioactivation of halogenated hydrocarbons by cytochrome P4502E1.

A physiologically based simulation approach for determining metabolic constants from gas uptake data.

Changes in the amount of cytochrome P450s in rat hepatic microsomes with starvation

DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. A Toxicological Profile for Xylene, Draft for Public Comment was released in September 2005. This edition supersedes any previously released draft or final profile. Toxicological profiles are revised and republished as necessary. For information regarding the update status of previously released profiles, contact ATSDR at: FOREWORD This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects information for the hazardous substance described therein. Each peer-reviewed profile identifies and reviews the key literature that describes a hazardous substance's toxicologic properties. Other pertinent literature is also presented, but is described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile begins with a public health statement that describes, in nontechnical language, a substance's relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance's health effects is described in a health effects summary. Data needs that are of significance to protection of public health are identified by ATSDR and EPA. Each profile includes the following: (A) The examination, summary, and interpretation of available toxicologic information and epidemiologic evaluations on a hazardous substance to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects; (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure that present a significant risk to human health of acute, subacute, and chronic health effects; and (C) Where appropriate, identification of toxicologic testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. The principal audiences for the toxicological profiles are health professionals at the Federal, State, …

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Papers

Enhanced activity of liver drug-metabolizing enzymes for aromatic and chlorinated hydrocarbons following food deprivation [Rats, toxicity].