Inhibition of Human Cytochrome P450 Enzymes by 1,2-Dithiole-3-thione, Oltipraz and Its Derivatives, and Sulforaphane

Langouët, Sophie; Furge, Laura Lowe; Kerriguy, Nathalie; Nakamura, Katsunori; Guillouzo, André; Fp, Guengerich

doi:10.1021/tx990189w

Cited by 106 publications

(61 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…At least two 1,2-dithiole-3-thiones have clinical applications, and this class of compounds has been extensively evaluated as anticarcinogens and antioxidants. Oltipraz (4-methyl-5-pyrazinyl-1,2-dithiole-3-thione) and related compounds have been used successfully to treat schistosomiasis and have been considered chemoprotective agents against a variety of cancers (33,40,44). Anetholedithione (5-[4-methoxyphenyl]-1,2-dithiole-3-thione) also has chemoprotective activity (46) and is used in many countries as a choleretic and to increase salivary flow (35).…”

Section: Discussionmentioning

confidence: 99%

1,2-Dithiole-3-Ones as Potent Inhibitors of the Bacterial 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH)

Reeve

Desai

et al. 2004

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The enzyme FabH catalyzes the initial step of fatty acid biosynthesis via a type II dissociated fatty acid synthase. The pivotal role of this essential enzyme, combined with its unique structural features and ubiquitous occurrence in bacteria, has made it an attractive new target for the development of antibacterial and antiparasitic compounds. We have searched the National Cancer Institute database for compounds bearing structural similarities to thiolactomycin, a natural product which exhibits a weak activity against FabH. This search has yielded several substituted 1,2-dithiole-3-ones that are potent inhibitors of FabH from both Escherichia coli (ecFabH) and Staphylococcus aureus (saFabH). The most potent inhibitor was 4,5-dichloro-1,2-dithiole-3-one, which had 50% inhibitory concentration (IC 50 ) values of 2 M (ecFabH) and 0.16 M (saFabH). The corresponding 3-thione analog exhibited comparable activities. Analogs in which the 4-chloro substituent was replaced with a phenyl group were also potent inhibitors, albeit somewhat less effectively (IC 50 values of 5.7 and 0.98 M for ecFabH and saFabH, respectively). All of the 5-chlorinated inhibitors were most effective when they were preincubated with FabH in the absence of substrates. The resulting enzyme-inhibitor complex did not readily regain activity after excess inhibitor was removed, suggesting that a slow dissociation occurs. In stark contrast, a series of inhibitors in which the 5-chloro substituent was replaced with the isosteric and isoelectronic trifluoromethyl group were poorer inhibitors (IC 50 values typically ranging from 25 to >100 M for both ecFabH and saFabH), did not require a preincubation period for maximal activity, and generated an enzymeinhibitor complex which readily dissociated. Possible modes of binding of 5-chloro-1,2-dithiole-3-ones and 5-chloro-1,2-dithiole-3-thiones with FabH which account for the role of the 5-chloro substituent were considered.Fatty acid biosynthesis, an essential process for all organisms, is catalyzed in plants and bacteria by a series of discrete dissociable enzymes and a central acyl carrier protein (ACP) (43). This set of enzymes is known collectively as a type II fatty acid synthase (FAS) and differs significantly from the type I FAS of metazoans, in which all of the enzymatic activities are contained on one or two polypeptides (12,31,67). The structural and mechanistic differences between the two FAS systems, in conjunction with the fact that the type I FAS is down regulated in well-nourished mammals (38, 39), have led to significant interest in components of the type II FAS as targets for the development of new antibacterial agents. Such agents may also have promise as novel antimalarials because protozoan parasites of the genus Plasmodium have been shown recently to contain a type II FAS in their apicoplast (53,62,63).Significant efforts and progress have been made in the understanding of small-molecule inhibition of two different components of the type II FAS. FabI (InhA), the enoyl ACP reductase that c...

show abstract

Section: Discussionmentioning

confidence: 99%

1,2-Dithiole-3-Ones as Potent Inhibitors of the Bacterial 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH)

Reeve

Desai

et al. 2004

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Precedence exists in the use of inhibitors of P450 19A1, which converts androgens to estrogens, as therapeutic agents in the treatment of estrogendependent tumors [30]. The drug oltipraz can block the activation of the mycotoxin aflatoxin B 1 in humans [31,32]. Although inhibition of P450s has potential in chemoprevention strategies, the application is still very limited.…”

Section: Roles Of P450s In Chemical Toxicitymentioning

confidence: 99%

Cytochrome P450 enzymes in drug metabolism and chemical toxicology: An introduction

Furge

Guengerich

2006

Biochem Molecular Bio Educ

Self Cite

143

View full text Add to dashboard Cite

Cytochrome P450 (P450) enzymes include a family of related enzymes that are involved in metabolism of vitamins, steroids, fatty acids, and other chemicals. This review presents a brief historical overview of the discovery and characterization of P450 enzymes extending from intermediary metabolism to the fields of drug metabolism and toxicology. Introductions to P450 enzyme structure and function are also presented. The goals of this review are to 1) provide an introduction to a few of the many aspects of P450 research relating to humans, 2) introduce additional ways of thinking about metabolism, 3) provide some basic examples of P450 enzymology, and 4) provide applications to topics widely taught in undergraduate courses in biochemistry.Keywords: Cytochrome P450 enzyme, drug metabolism, chemical toxicity, P450 mechanism.Cytochrome P450 (P450) 1 enzymes are a family of heme-containing proteins found from bacteria to human. In mammals, the enzymes are membrane-bound (usually in the endoplasmic reticulum, although the seven in Families 11, 24, and 27 are found in mitochondria; Table I). P450s serve a variety of functions including steroid, fatty acid, eicosanoid, and vitamin A and D metabolism as well as metabolism of foreign compounds including natural products, pharmaceuticals, and carcinogens. P450s are found in every tissue except skeletal muscle and red blood cells [1]. With the completion of the human genome sequence project, there appear to be 57 distinct P450 genes in humans [2]. Of these, about 13 are "orphan" P450s for which the metabolic function is not yet known [3].There is wide interest in P450s due to applications in a variety of fields including biochemistry, biotechnology, chemistry, environmental sciences, enzymology, microbiology, physiology, pharmacology, plant sciences, and toxicology. Indeed, in the last decade alone, there were more than 1000 publications per year relating to P450s. This review will highlight the roles of human P450s in drug metabolism and chemical toxicity and applications to undergraduate studies. References to more in-depth reviews are also provided. DISCOVERY AND PURIFICATIONThe history of P450 can be traced back to questions related to the metabolism of steroids, drugs, and carcinogens in the 1940s. Early studies of difficult alkyl oxidations of amino acids and fatty acids, such as oxidation at the terminal methyl group of a fatty acid, allowed for the isolation of cell-free extracts capable of performing NAD(P)Hdependent oxidation reactions [4]. The "mixed-function oxidase" stoichiometry.that is now recognized as the basic reaction catalyzed by a P450 was not immediately obvious. In particular, the requirement for a reduced pyridine nucleotide to achieve an overall oxidation was surprising at the time. The concept of mixed-function oxidation was developed by O. Hayaishi et al. in Japan [5] and H. Mason in the U.S [6]. Subsequently, such reactions were shown to occur with steroids and xenobiotics, particularly drugs (J. Axelrod and B. Brodie et al.) [7,8] and carcinogen...

show abstract

“…Monofunctional inducers (phenols, lactones, isothiocyanates, dithiocarbamates, dithiins, and 1,2-dithiole-3-thiones) elevate phase 2 enzymatic activities without significantly elevating the aforementioned phase 1 activities and do not possess an obvious defining structural characteristic. Several, but not all, phase 2 enzyme inducers have also been shown to inhibit the activities of some cytochrome P450 enzymes [36,37], but the contribution of this component to their chemoprotective actions in vivo may be limited [38].…”

Section: Mechanisms Of Phase 2 Enzyme Induction By Dithiolethionesmentioning

confidence: 99%

Role of phase 2 enzyme induction in chemoprotection by dithiolethiones

Kwak

Egner

Dolan

et al. 2001

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

227

127

View full text Add to dashboard Cite

One of the major mechanisms of protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), UDP-glucuronosyl transferases, and quinone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieved by administering any of a diverse array of naturally-occurring and synthetic chemopreventive agents. Indeed, monitoring of enzyme induction has led to the recognition or isolation of novel, potent chemopreventive agents such as 1,2-dithiole-3-thiones, terpenoids and the isothiocyanate sulforaphane. For example, oltipraz, a substituted 1,2-dithiole-3-thione originally developed as an antischistosomal agent, possesses chemopreventive activity against different classes of carcinogens targeting multiple organs. Mechanistic studies in rodent models for chemoprevention of aflatoxin B 1 (AFB 1 )-induced hepatocarcinogenesis by oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 activation of AFB 1 can also contribute to protection. Exposure of rodents to 1,2-dithiole-3-thiones triggers nuclear accumulation of the transcription factor Nrf2 and its enhanced binding to the "antioxidant response element" (ARE), leading to transcriptional activation of a score of genes involved in carcinogen detoxication and attenuation of oxidative stress. Nrf2-deficient mice fail to induce many of these genes in response to dithiolethiones; moreover, basal expression of these genes is typically repressed. To test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans, three key elements are necessary: a candidate agent, an at-risk population and modulatable intermediate endpoints. Towards this end, a placebo-controlled, double blind clinical trial of oltipraz was conducted in residents of Qidong, PR China who are exposed to dietary aflatoxins and who are at high risk for the development of liver cancer. Oltipraz significantly enhanced excretion of a phase 2 product, aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of study participants administered 125 mg oltipraz by mouth daily. Administration of 500 mg oltipraz once a week led to a significant reduction in the excretion of the primary oxidative metabolite of AFB 1 , AFM 1 , when measured shortly after drug administration. While this study highlighted the general feasibility of inducing phase 2 enzymes in humans, a longer term intervention is addressing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time in this high-risk population.

show abstract

Inhibition of Human Cytochrome P450 Enzymes by 1,2-Dithiole-3-thione, Oltipraz and Its Derivatives, and Sulforaphane

Cited by 106 publications

References 39 publications

1,2-Dithiole-3-Ones as Potent Inhibitors of the Bacterial 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH)

1,2-Dithiole-3-Ones as Potent Inhibitors of the Bacterial 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH)

Cytochrome P450 enzymes in drug metabolism and chemical toxicology: An introduction

Role of phase 2 enzyme induction in chemoprotection by dithiolethiones

Contact Info

Product

Resources

About