Direct enzyme-catalyzed reduction of anthracyclines by reduced nicotinamide adenine dinucleotide

Fisher, Jed F.; Ramakrishnan, K.; Becvar, James E.

doi:10.1021/bi00275a005

Cited by 32 publications

(22 citation statements)

References 41 publications

(63 reference statements)

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“…The quinone methide may be envisioned to behave as a nucleophile, to react with an electrophile to yield a C-7 functionalized quinone; or to behave as an electrophile to yield a C-7 functionalized hydroquinone. This latter hydroquinone may re-eliminate to the quinone methide unless a suitable oxidant is present to convert this adduct to the stable quinone state (12,13). If no suitable reagent to react with the quinone methide is present, it will react with a proton (an electrophile) to provide a 7-deoxy aglycone or react with itself to provide a 7,7'-dimer.…”

Section: I< 2cmentioning

confidence: 99%

“…The forination of a stable adduct from nucleophilic trapping of the quinone methide requires a subsequent oxidation step; the subtleties of these reactions are discussed elsewhere (12). Only one nucleophile, N-acrtylcysteine, has been found thus far to have significant bimolecular reactivity to this quinone methide (K. Ramakrishnan Aclacinomycin A is the representative anthracycline from the second anthracycline family with respect to quinone methide reactivity, the 11-deoxy anthracyclines.…”

Section: I< 2cmentioning

confidence: 99%

“…Aglycone precipitation may be quite competitive with reduction. Nonetheless under the appropriate experimental circumstances the competence of the anthracyclines for overall two electron reduction is easily established (44,45); moreover their competence in the elimination reaction to the 7-deoxy aglycone quinone methide tautomer is firmly established (12,16,17). Thus while the semiquinone has not been excluded from this reaction, neither is there any evidence that demands it be included.…”

Section: Chemistry Of the Anthracycline Semiquinonementioning

confidence: 99%

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A chemical perspective on the anthracycline antitumor antibiotics.

Abdella¹,

Fisher²

1985

Environ Health Perspect

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The anthracycline antitumor antibiotics occupy a central position in the chemotherapeutic control of cancer. They remain, however, antibiotics of the last resort and thus exhibit toxicity both to the neoplasm and to the host organism. As part of the continuing effort to dissociate the molecular processes responsible for these two separate toxicities, attention has been drawn to the intrinsic redox capacity of their tetrahydronapthacenedione aglycone moiety, and to the possible expression of this redox activity against those biomolecules for which anthracyclines have a particular affinity (polynucleotides and membranes). This review is a synopsis of the present trends and thoughts concerning this relationship, written from the point of view of the intrinsic chemical competence of the anthracyclines and their metabolites. While our ignorance is profound-the precise molecular locus of the antitumor expression of the anthracyclines remains unknown-there is now evidence that the relationship of the anthracyclines to the DNA (possibly requiring enzymatic cooperation) and to the membranes, with neither event requiring redox chemistry, may comprise the core of the antitumor effects. The adventitious expression of the redox activity under either aerobic conditions (in which circumstances molecular oxygen is reduced) or anaerobic conditions (in which circumstances potentially reactive aglycone tautomers are obtained) is therefore thought to contribute more strongly to the host toxicity. Yet little remains proven, and the understanding of the intrinsic chemical competence can do little more than lightly define the boundaries within which are found these and numerous other working hypotheses.

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Section: I< 2cmentioning

confidence: 99%

Section: I< 2cmentioning

confidence: 99%

Section: Chemistry Of the Anthracycline Semiquinonementioning

confidence: 99%

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A chemical perspective on the anthracycline antitumor antibiotics.

Abdella¹,

Fisher²

1985

Environ Health Perspect

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“…Both the four-membered anthracycline ring of Adriamycin and the three-membered isoalloxazine ring of riboflavin including its physiological derivatives, FMN and FAD, form a 1: 11 stoichiometric complex in vitro (7). Adriamycin and some of its metabolites can mimic flavins to complete successfully for binding sites in certain flavin-containing enzymes (8,9). On the other hand, flavoenzymes are responsible for catabolizing anthracycline drugs.…”

mentioning

confidence: 99%

“…Under these conditions, inadequate synthesis of FAD possibly may interfere with mitochondria1 electron transport which is needed for maintaining oxidative phosphorylation in metabolically active tissues. Furthermore, Adriamycin competes for binding with flavins on flavoenzymes and may also exacerbate riboflavin deficiency (8,9).…”

mentioning

confidence: 99%

Enhancement of Adriamycin-Induced Mortality during Riboflavin Administration and Riboflavin Deficiency in Rats

Raiczyk

Rivlin

Pinto

1988

Experimental Biology and Medicine

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Adriamycin-treated rats were monitored for survivorship while consuming a normal diet adequate in riboflavin, a normal diet and receiving daily high-dose injections of riboflavin-5'-phosphate (flavin mononucleotide, FMN), or a riboflavin-deficient diet. Each animal was compared to a corresponding pair-fed, saline-treated control. In Adriamycintreated rats fed the normal chow diet alone, survivorship declined within 7 days and remained constant after 12 days to about 50%. Adriamycin-treated rats consuming the normal diet and injected with FMN initially showed similar survivorship; however, after 20 days survival fell to 14%. Adriamycin-treated, riboflavin-deficient rats showed within 5 days a precipitous decline in survivorship which leveled to 5%. These results suggest that during Adriamycin treatment, proper riboflavin nutriture may be a crucial determinant of survival. o 1988 Society for Experimental Biology and Medicine. 495

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New approaches to the possible prevention of side effects of chemotherapy by nutrition

Pinto¹,

Raiczyk²,

Huang³

et al. 1986

Cancer

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In an effort to develop new methods for preventing side effects of chemotherapy, the authors initiated studies to determine whether Adriamycin (doxorubicin) inhibits the metabolism of riboflavin (vitamin B2). Adriamycin has been shown to form a 1:1 stoichiometric complex with riboflavin, as well as to compete for binding to tissue proteins. Adult rats treated with Adriamycin in clinically relevant doses were compared to control animals in ability to convert riboflavin into flavin adenine dinucleotide (FAD), the active flavin coenzyme derivative, in heart, skeletal muscle, liver, and kidney. Rats treated with Adriamycin exhibited diminished formation of carbon 14 (14C)FAD in skeletal muscle to nearly 50% that of controls, and in heart to about 70% to 80% of controls. Under these conditions, (14C)FAD formation in liver and kidney was largely unaffected by Adriamycin. In preliminary studies, riboflavin-deficient animals treated with Adriamycin had accelerated mortality rates compared to those of food restricted controls treated with similar doses of Adriamycin. The data as a whole suggest a potential mechanism for Adriamycin-induced cardiac and skeletal myopathy, i.e., inhibition of synthesis of FAD, a flavin coenzyme which is involved in electron transport, lipid metabolism, and energy generation. These findings in an animal model raise the possibility that defects of riboflavin nutriture, either dietary or drug-induced, may be a determinant of Adriamycin toxicity. Further studies are required to explore the potential for preventing side effects due to Adriamycin by administration of this vitamin.

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Direct enzyme-catalyzed reduction of anthracyclines by reduced nicotinamide adenine dinucleotide

Cited by 32 publications

References 41 publications

A chemical perspective on the anthracycline antitumor antibiotics.

A chemical perspective on the anthracycline antitumor antibiotics.

Enhancement of Adriamycin-Induced Mortality during Riboflavin Administration and Riboflavin Deficiency in Rats

New approaches to the possible prevention of side effects of chemotherapy by nutrition

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