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Research Communication

Administration of the Oral Antibiotic Frenolicin-B Selectively Alters Copper Nutriture in Male Rats

David C. Kossor^*,, Shenggao Han, Francis W. Kemp, Richard W. Slauter^**, David Serota, Daniel Rajaskarian, Nicholas Milner^*, Alberto Davidovich^* and John D. Bogden^1,

^* Roche Vitamins Incorporated, Nutley, NJ 07110; Department of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School, Newark, NJ 07103; ^** Battelle, Incorporated, Columbus, OH 43201; and MPI Research LLC, Mattawan, MI 49071

¹To whom correspondence should be addressed. E-mail: bogden{at}umdnj.edu.

The polyketide antibiotic Frenolicin-B (FB) produces anorexia and esophageal epithelial hyperplasia (EH) in rats, findings that are characteristic of zinc deficiency. Because FB also chelates divalent cations in vitro, we conducted studies to determine whether FB modifies blood and organ concentrations of zinc and other essential metals (calcium, copper, iron and magnesium). Groups of male Sprague-Dawley rats (250g; n = 20/group) consumed diets with adequate (40 µg/g), deficient (<2 µg/g) or fortified (100 µg/g) zinc concentrations ad libitum for 28 d. Two groups fed either Zn-adequate or Zn-fortified diets also were given 100 mg/(kg · d) of FB in diet, and 2 groups were pair-fed controls. Histopathology or metal analyses were performed on tissues from 10 rats/group. FB caused EH of the nonglandular stomach but not of other tissues. Of the metals evaluated, only copper concentrations were significantly reduced in all tissues examined except kidney. A broad range of kidney copper concentrations was found; these concentrations were associated with plasma copper and proteinaceous deposits within tubules. In rats, FB substantially and selectively depletes Cu in vivo, suggesting that drugs with structures that permit metal chelation should be evaluated for their potential to alter trace metal nutriture.

KEY WORDS: • copper • Frenolicin-B • antibiotics • rats