Ultrastructure of penicillamine-induced skin lesions

Hashimoto, Ken; McEvoy, Bernard; Belcher, Richard W.

doi:10.1016/s0190-9622(81)80176-4

Cited by 53 publications

(24 citation statements)

References 21 publications

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“…In the rofecoxib-treated group, the elastic lamellae in the tunica media of the thoracic aorta were focally disrupted, resulting in a greater degree of branching than those in the control aorta. These observations are similar to the findings in animals and humans under conditions inhibiting cross-linking of elastin fibers (Herd and Orbison, 1966;Andrews et al, 1975;Hashimoto et al, 1981;Light et al, 1986;Yoshikawa et al, 2001). In our previous report (Oitate et al, 2006), we demonstrated that the radioactivity from [ 14 C]rofecoxib was localized on the elastic fibers of rat aortas by microautoradiography and that the accumulation of radioactivity in the aortas increased in a dosefrequency-dependent manner.…”

Section: Discussionsupporting

confidence: 88%

“…7A). It has been demonstrated that the prevention of this cross-linking in elastin causes serious lesions of connective tissues in animals and humans (Herd and Orbison, 1966;Andrews et al, 1975;Hashimoto et al, 1981;Junker et al, 1982;Light et al, 1986;Yoshikawa et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that an anti-rheumatic amino thiol, D-penicillamine, reacts with the aldehyde group of allysine to form a thiazolidine-type complex (Pinnell et al, 1968;Deshmukh and Nimni, 1969;Howard-Lock et al, 1986). Chronic administration of this compound has also been known to cause deep lesions in the connective tissues, such as angiopathy and pseudoxanthoma elasticum in rats and humans (Hashimoto et al, 1981;Junker et al, 1982;Light et al, 1986). From this information, we hypothesized that rofecoxib and/or its metabolite(s) might also form a covalent adduct with allysine in elastin and cause damage to the elastin.…”

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confidence: 99%

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Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Oitate¹,

Hirota²,

Takahashi³

et al. 2006

J Pharmacol Exp Ther

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We have previously reported that oral administration of [14 C]rofecoxib to rats resulted in the long retention of radioactivity by the aorta as a consequence of covalent binding to elastin. Treatment of rats with ␣-phenyl-␣-propylbenzeneacetic acid 2-[diethylamino]-ethyl ester hydrochloride (SKF-525A), a cytochrome P450 inhibitor, significantly decreased the systemic exposure of 5-hydroxyrofecoxib, one of the main metabolites of rofecoxib, whereas there was no statistically significant change in the retention of radioactivity from [14 C]rofecoxib in the aorta. On the other hand, the aortic retention of radioactivity closely correlated to the systemic exposure of unchanged rofecoxib in the dose range between 2 and 10 mg/kg. A covalent binding study of [14 C]rofecoxib in vitro using rat aorta homogenate in the presence of D-penicillamine, hydralazine, ␤-aminopropionitrile, and sodium borohydride suggested that the aldehyde group of allysine in elastin was relevant to the covalent binding. In a model reaction using benzaldehyde, rofecoxib but not 5-hydroxyrofecoxib reacted with the aldehyde group of benzaldehyde in a manner of condensation reaction under a physiological pH condition. A histopathological examination using an electron microscope demonstrated that multiple oral administration of rofecoxib to rats caused marked degradation of the elastic fiber system of the aorta. These results suggested that rofecoxib as such is reactive in vivo, undergoing a condensation reaction with allysine, thereby preventing the formation of cross-linkages in elastin, i.e., desmosine and isodesmosine, and causing the degradation of the elastic fibers.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Oitate¹,

Hirota²,

Takahashi³

et al. 2006

J Pharmacol Exp Ther

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“…Collagen abnormalities have occasionally been reported [16]. This so-called ‘lumpy-bumpy’ [11]or ‘bramble-bush’ pattern [17]appears to be specific of DPA-induced disorders [5]and can be related to the mechanism of action of the drug.…”

Section: Discussionmentioning

confidence: 99%

Elastosis perforans serpiginosa Associated with Pseudo-Pseudoxanthoma elasticum during Treatment of Wilson’s Disease with Penicillamine

Bécuwe¹,

Dalle²,

Ronger-Savlé³

et al. 2005

Dermatology

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Background: Elastosis perforans serpiginosa (EPS) is a reactive perforating dermatosis characterized by the elimination of abnormal elastic fibers from the upper dermis through the epidermis. In a few cases, it occurs as a side effect of treatment by D-penicillamine (DPA). The first case of EPS induced by DPA was described in 1972 in a patient treated for Wilson’s disease. Subsequently, cutaneous changes resembling pseudoxanthoma elasticum (PXE) were observed in patients treated with DPA and were reported as pseudo-PXE. Case Report: We report herein the clinical, pathological and ultrastructural study of 2 new cases of DPA-induced EPS and pseudo-PXE. These patients had been treated for Wilson’s disease since 14 and 16 years, respectively. Characteristic abnormal elastic fibers were found on histopathological examination of both EPS and pseudo-PXE skin and confirmed by an ultrastructural study. There was no ABCC6 mutation. Discussion: Penicillamine is able to induce widespread, cutaneous and systemic, elastic fiber damage. Our patients present typical features of DPA-induced elastosis, presenting as EPS and pseudo-PXE. ABCC6 mutation is associated with PXE and, as expected, it was absent in our cases of pseudo-PXE. This elastopathy has been related to morphologic changes in elastic fibers secondary to prolonged therapy in most cases. DPA may interfere with elastin cross-linking through inhibition of the enzyme lysyl oxidase, or by formation of complexes with the cross-linked precursors, impairing a normal maturation of elastic fibers. However, no fatal complication of DPA-induced elastopathy has been reported so far. An improvement of the cutaneous lesions is expected after the drug discontinuation.

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“…1A). It has been reported that the prevention of these cross-linkages in elastin or collagen causes serious lesions in the connective tissues in animals and humans (Herd and Orbison, 1966;Andrews et al, 1975;Hashimoto et al, 1981;Junker et al, 1982;Light et al, 1986;Yoshikawa et al, 2001). In fact, multiple oral administration of rofecoxib to rats caused a marked degradation of the elastic fibers in the aorta in vivo, conceivably by covalently binding to allysine aldehyde and by the inhibition of the normal cross-linking process of elastin (Oitate et al, 2007).…”

mentioning

confidence: 99%

Covalent Binding of Rofecoxib, but Not Other Cyclooxygenase-2 Inhibitors, to Allysine Aldehyde in Elastin of Human Aorta

Oitate¹,

Hirota²,

Murai³

et al. 2007

Drug Metab Dispos

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ABSTRACT:In rats, it has been reported that rofecoxib, a cyclooxygenase-2 (COX-2) inhibitor, reacts with the aldehyde group of allysine in elastin to give a condensation covalent adduct, thereby preventing the formation of cross-linkages in the elastin and causing degradation of the elastic fibers in aortas in vivo. Acid, organic solvent, and proteolytic enzyme treatments of human aortic homogenate after incubation with

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Ultrastructure of penicillamine-induced skin lesions

Cited by 53 publications

References 21 publications

Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Mechanism for Covalent Binding of Rofecoxib to Elastin of Rat Aorta

Elastosis perforans serpiginosa Associated with Pseudo-Pseudoxanthoma elasticum during Treatment of Wilson’s Disease with Penicillamine

Covalent Binding of Rofecoxib, but Not Other Cyclooxygenase-2 Inhibitors, to Allysine Aldehyde in Elastin of Human Aorta

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