Inhibition of mitochondrial carnitine palmitoyltransferases by adriamycin and adriamycin analogues

Khosrow Kashfi, Mervyn Israel, Trevor W. Sweatman, Ramakrishnan Seshadri, George Cook

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Adriamycin (ADR; doxorubicin) and its highly lipophilic, less toxic analogue N-benzyladriamycin-14-valerate (AD 198) were found to inhibit rat heart and liver carnitine palmitoyltransferases of both mitochondrial outer and inner membranes. The outer membrane enzyme was more sensitive to inhibition by these drugs than the inner membrane enzyme, and AD 198 was a more potent inhibitor of these enzymes than ADR. Other analogues of ADR, N-trifluoroacetyladriamycin-14-valerate (AD 32) and N-trifluoroacetyladriamycin-14-O-hemiadipate (AD 143), which are documented as being noncardiotoxic, were also more potent inhibitors of the mitochondrial carnitine palmitoyltransferases than ADR. Overall, the cardiac mitochondrial carnitine palmitoyltransferases seemed to be slightly more sensitive to the inhibitory effects of ADR and its analogues than the liver enzyme. ADR was an uncompetitive inhibitor with respect to palmitoyl-CoA and a noncompetitive inhibitor with respect to carnitine for both mitochondrial outer and inner membrane enzymes. Our data suggest that mitochondria can take up ADR and concentrate it within the matrix, as is known to happen with other positively-charged compounds. More ADR was found associated with the mitochondrial inner membrane than with the outer membrane; this could be due to the greater protein content of the inner membrane rather than drug binding to cardiolipin. Although inhibition of cardiac inner membrane carnitine palmitoyltransferase has been implicated previously as part of the cardiotoxicity mechanism of ADR, the present findings with ADR and its noncardiotoxic analogues do not support this view.

Original languageEnglish (US)
Pages (from-to)1441-1448
Number of pages8
JournalBiochemical Pharmacology
Volume40
Issue number7
DOIs
StatePublished - Oct 1 1990

Fingerprint

Carnitine O-Palmitoyltransferase
Mitochondrial Membranes
valrubicin
Doxorubicin
Membranes
Enzymes
Palmitoyl Coenzyme A
Cardiolipins
Liver
Carnitine
Poisons
Enzyme Inhibitors
Pharmaceutical Preparations
Mitochondria
Rats
N-benzyladriamycin-14-valerate
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Inhibition of mitochondrial carnitine palmitoyltransferases by adriamycin and adriamycin analogues. / Kashfi, Khosrow; Israel, Mervyn; Sweatman, Trevor W.; Seshadri, Ramakrishnan; Cook, George.

In: Biochemical Pharmacology, Vol. 40, No. 7, 01.10.1990, p. 1441-1448.

Research output: Contribution to journalArticle

Kashfi, Khosrow ; Israel, Mervyn ; Sweatman, Trevor W. ; Seshadri, Ramakrishnan ; Cook, George. / Inhibition of mitochondrial carnitine palmitoyltransferases by adriamycin and adriamycin analogues. In: Biochemical Pharmacology. 1990 ; Vol. 40, No. 7. pp. 1441-1448.
@article{277580ac7efd40e4b5b7eeb71a443495,
title = "Inhibition of mitochondrial carnitine palmitoyltransferases by adriamycin and adriamycin analogues",
abstract = "Adriamycin (ADR; doxorubicin) and its highly lipophilic, less toxic analogue N-benzyladriamycin-14-valerate (AD 198) were found to inhibit rat heart and liver carnitine palmitoyltransferases of both mitochondrial outer and inner membranes. The outer membrane enzyme was more sensitive to inhibition by these drugs than the inner membrane enzyme, and AD 198 was a more potent inhibitor of these enzymes than ADR. Other analogues of ADR, N-trifluoroacetyladriamycin-14-valerate (AD 32) and N-trifluoroacetyladriamycin-14-O-hemiadipate (AD 143), which are documented as being noncardiotoxic, were also more potent inhibitors of the mitochondrial carnitine palmitoyltransferases than ADR. Overall, the cardiac mitochondrial carnitine palmitoyltransferases seemed to be slightly more sensitive to the inhibitory effects of ADR and its analogues than the liver enzyme. ADR was an uncompetitive inhibitor with respect to palmitoyl-CoA and a noncompetitive inhibitor with respect to carnitine for both mitochondrial outer and inner membrane enzymes. Our data suggest that mitochondria can take up ADR and concentrate it within the matrix, as is known to happen with other positively-charged compounds. More ADR was found associated with the mitochondrial inner membrane than with the outer membrane; this could be due to the greater protein content of the inner membrane rather than drug binding to cardiolipin. Although inhibition of cardiac inner membrane carnitine palmitoyltransferase has been implicated previously as part of the cardiotoxicity mechanism of ADR, the present findings with ADR and its noncardiotoxic analogues do not support this view.",
author = "Khosrow Kashfi and Mervyn Israel and Sweatman, {Trevor W.} and Ramakrishnan Seshadri and George Cook",
year = "1990",
month = "10",
day = "1",
doi = "10.1016/0006-2952(90)90438-Q",
language = "English (US)",
volume = "40",
pages = "1441--1448",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "7",

}

TY - JOUR

T1 - Inhibition of mitochondrial carnitine palmitoyltransferases by adriamycin and adriamycin analogues

AU - Kashfi, Khosrow

AU - Israel, Mervyn

AU - Sweatman, Trevor W.

AU - Seshadri, Ramakrishnan

AU - Cook, George

PY - 1990/10/1

Y1 - 1990/10/1

N2 - Adriamycin (ADR; doxorubicin) and its highly lipophilic, less toxic analogue N-benzyladriamycin-14-valerate (AD 198) were found to inhibit rat heart and liver carnitine palmitoyltransferases of both mitochondrial outer and inner membranes. The outer membrane enzyme was more sensitive to inhibition by these drugs than the inner membrane enzyme, and AD 198 was a more potent inhibitor of these enzymes than ADR. Other analogues of ADR, N-trifluoroacetyladriamycin-14-valerate (AD 32) and N-trifluoroacetyladriamycin-14-O-hemiadipate (AD 143), which are documented as being noncardiotoxic, were also more potent inhibitors of the mitochondrial carnitine palmitoyltransferases than ADR. Overall, the cardiac mitochondrial carnitine palmitoyltransferases seemed to be slightly more sensitive to the inhibitory effects of ADR and its analogues than the liver enzyme. ADR was an uncompetitive inhibitor with respect to palmitoyl-CoA and a noncompetitive inhibitor with respect to carnitine for both mitochondrial outer and inner membrane enzymes. Our data suggest that mitochondria can take up ADR and concentrate it within the matrix, as is known to happen with other positively-charged compounds. More ADR was found associated with the mitochondrial inner membrane than with the outer membrane; this could be due to the greater protein content of the inner membrane rather than drug binding to cardiolipin. Although inhibition of cardiac inner membrane carnitine palmitoyltransferase has been implicated previously as part of the cardiotoxicity mechanism of ADR, the present findings with ADR and its noncardiotoxic analogues do not support this view.

AB - Adriamycin (ADR; doxorubicin) and its highly lipophilic, less toxic analogue N-benzyladriamycin-14-valerate (AD 198) were found to inhibit rat heart and liver carnitine palmitoyltransferases of both mitochondrial outer and inner membranes. The outer membrane enzyme was more sensitive to inhibition by these drugs than the inner membrane enzyme, and AD 198 was a more potent inhibitor of these enzymes than ADR. Other analogues of ADR, N-trifluoroacetyladriamycin-14-valerate (AD 32) and N-trifluoroacetyladriamycin-14-O-hemiadipate (AD 143), which are documented as being noncardiotoxic, were also more potent inhibitors of the mitochondrial carnitine palmitoyltransferases than ADR. Overall, the cardiac mitochondrial carnitine palmitoyltransferases seemed to be slightly more sensitive to the inhibitory effects of ADR and its analogues than the liver enzyme. ADR was an uncompetitive inhibitor with respect to palmitoyl-CoA and a noncompetitive inhibitor with respect to carnitine for both mitochondrial outer and inner membrane enzymes. Our data suggest that mitochondria can take up ADR and concentrate it within the matrix, as is known to happen with other positively-charged compounds. More ADR was found associated with the mitochondrial inner membrane than with the outer membrane; this could be due to the greater protein content of the inner membrane rather than drug binding to cardiolipin. Although inhibition of cardiac inner membrane carnitine palmitoyltransferase has been implicated previously as part of the cardiotoxicity mechanism of ADR, the present findings with ADR and its noncardiotoxic analogues do not support this view.

UR - http://www.scopus.com/inward/record.url?scp=0025042347&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025042347&partnerID=8YFLogxK

U2 - 10.1016/0006-2952(90)90438-Q

DO - 10.1016/0006-2952(90)90438-Q

M3 - Article

VL - 40

SP - 1441

EP - 1448

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 7

ER -