Differences in the Nephrotoxicity of Hydroquinone Among Fischer 344 and Sprague-Dawley Rats and B6c3f1 Mice

Abstract

The present studies indicate pronounced species-, sex-, and strain- related differences in the acute nephrotoxicity of hydroquinone (HQ) when administered by gavage to male and female Sprague-Dawley (SD) rats, Fischer 344 (F344) rats, and B6C3F1 mice. Following a single dose of 400 mg/kg, male and female F344 rats displayed pronounced enzymuria and glucosuria. In female F344 rats, urinary alkaline phosphatase and glucose were the most sensitive indicators of renal toxicity, reaching levels of, respectively, 157 times and 137 times control values within 24 h of dosing. HQ treatment of male F344 rats also resulted in significant enzymuria, although it was less marked than that seen in female F344 rats. Significant numbers of epithelial cells were also present in the urine from F344 rats at 200 (female) or 400 mg/kg (male and female). SD rats did not show evidence of elevated levels of urinary enzymes or increased blood urea nitrogen (BUN) after oral administration of HQ at a dose level of 400 mg/kg. Oral administration of HQ to male and female B6C3F1 mice at 350 mg/kg resulted in only slight but significant increases in BUN.

The effect of oxygen tension on the cytotoxicity of hydroquinone and selected hydroquinone metabolites to isolated rat renal proximal tubular cells

“…Male F344 rats were found to be more sensitive than male SD rats to the cytotoxicity of HQ when incubated under atmospheres containing 95% O 2 / 5% CO 2, showing a significantly increased response at the 0.15-mM exposure concentration over that seen in the SD rat. This relative strain sensitivity correlates with published in vivo results for HQ (Boatman et al 1996). In addition, when incubated under 95% O 2 atmospheres, Cys-HQ and NAcCys-HQ (but not TriGS-HQ) produced slight but detectable amounts of cytotoxicity at incubation concentrations of 0.15 mM (Fig.…”

“…A significant strain difference was detected with PT cells from the F344 rat showing greater sensitivity to HQ [lowest observed effect concentration (LOEC)=0.15 mM; no observed effect concentration (NOEC)=0.05 mM] than cells from SD rats (LOEC=0.5 mM; NOEC=0.15 mM). This relative strain sensitivity correlates with in vivo results for HQ (Boatman et al 1996) and suggests an oxygen-mediated mechanism as a potential contributing factor to the strain-related differences in acute nephrotoxicity observed in vivo.…”

“…1) produce patterns of renal tubule cell degeneration, enzymuria, and glucosuria in Fischer F344 (F344) rats, indicative of proximal tubular (PT)-cell toxicants (Lau et al 1988;National Toxicology Program 1989;English et al 1994;Boatman et al 1996). The underlying mechanism for this effect is not currently known; however, conjugation with glutathione appears to be necessary for the toxicity (Lau et al 1988).…”

“…The relatively weak acute nephrotoxic response to HQ displayed by the F344 strain of rat is absent in similarly treated Sprague-Dawley (SD) rats (Boatman et al 1996). Nephrotoxicity is manifested following a single acute oral dose as increased blood urea nitrogen, glucosuria, and proteinuria.…”

DNA adduct formation by ochratoxin A: Review of the available evidence

“…Moreover, OTA-derived S-conjugates which may be directed to the kidney could not be detected (Zepnik et 2005b). The involvement of a nephrotoxic S-conjugate in OTA toxicity and carcinogenicity is also not consistent with the potency of other hydroquinones activated by a glutathione-conjugation pathway, which usually require administration of much higher doses to induce nephrotoxicity (English et al 1994;Monks and Lau 1994;Boatman et al 1996) and/or renal tumours. Furthermore, it is well established that nephrotoxic hydroquinone S-conjugates promote tumour formation by inducing sustained regenerative cell proliferation in response to cytotoxicity and tissue necrosis, which is also not consistent with the histopathological changes observed after treatment with OTA (NTP 1989;Boorman et al 1992;English et al 1994;Nakagawa et al 1998;Lock and Hard 2004).…”