Covalent Protein Adducts of Hydroquinone in Tissues from Rats:  Quantitation of Sulfhydryl-Bound Forms following Single Gavage or Intraperitoneal Administration or Repetitive Gavage Administration

Abstract

The current studies were conducted to investigate the degree and type of protein binding of hydroquinone (HQ) in the rat following single oral or intraperitoneal (ip) or repeated oral administrations. Male or female F-344 rats or male SD rats received a single dose of HQ at 0, 25, 50, or 100 mg/kg by either gavage or ip injection (SD rats only). In addition, male or female F-344 or male SD rats received HQ by gavage for 6 weeks (5 days/week) at 0, 25, or 50 mg/kg/day. Sulfhydryl-bound HQ was quantitated in protein from blood, kidneys, livers, or spleens 24 h after treatment using an alkaline permethylation procedure. The amount of total protein-S adducts increased with increasing dose in all the tissues that were assayed. Female rats had higher levels of adducts in blood, livers, and kidneys than did male rats when they were treated orally. Male F-344 rats treated orally had elevated levels of adducts in these same tissues compared to SD rats treated orally. For all genders and strains of rats and for all treatment regimens, mono-adducts predominated in livers (>72% of total). In the kidneys, tri- and tetrasubstituted adducts predominated with the summation accounting for >60% of the total. Ip administration of HQ resulted in significantly elevated levels of adducts in all the tissues that were examined, with the greatest increases seen for protein from blood and spleens. Levels of protein-S adducts of HQ in rat kidney following a single gavage administration correlated well with previously published differences in acute HQ nephrotoxicity in rats (female F-344 rat > male F-344 rat > male SD rat). Elevated levels of HQ protein-S adducts following repeated gavage administration did not correlate to measurable clinical signs of nephrotoxicity. Evidence is presented suggesting a possible role for the prostaglandin H synthase complex in the metabolic activation of HQ. In addition, protein arylation alone cannot account for the greater sensitivity of male F-344 rats toward chronic administration of HQ. The sensitivity of male F-344 rats to HQ is likely due to other factors, including the incidence and severity of chronic progressive nephropathy.

Evidence of a new dechlorinated ochratoxin A derivative formed in opossum kidney cell cultures after pretreatment by modulators of glutathione pathways: Correlation with DNA‐adduct formation

“…HQ are further metabolized by four pathways [43]: glucuronide conjugation, sulfoconjugation, oxidative conversion of HQ into benzoquinone (BQ), or cycloxygenase (COX)-mediated oxidation [44] followed by conjugation with GSH, which leads to metabolic activation, producing intermediates which are nephrotoxic [45]. Subsequent metabolism of the GSH conjugates via GGT and dipeptidase conjugate of HQ is an important determinant of the internal dose of these metabolites [46]. This last mechanism could be blocked by ACIVICIN.…”

Reactivity of Contact Allergenic Haptens to Amino Acid Residues in a Model Carrier Peptide, and Characterization of Formed Peptide-Hapten Adducts¹

“…But the reported type I haptens are generally not ·,ß-unsaturated carbonyl compounds [7]. It is well known that thiols are usually better nucleophiles than amines [13], and the addition readiness of cysteine to ·,ß-unsaturated carbonyl compounds has been investigated [14][15][16][17][18][19][20].…”

Electrophile tocopheryl quinones in apoptosis and mutagenesis: Thermochemolysis of thiol adducts with proteins and in cells

“…An alternative approach to identifying adducts derives from a base-cleavage reaction for naturally occurring adducts that was first described in 1933 (10). From this early work, a multistep procedure was developed (base-cleavage followed by permethylation with methyl iodide) to show adduct formation with benzoquinone and substituted benzoquinones, although this method requires from 20-to 200-mg quantities of protein (11)(12)(13). We recently described a method to identify adducts between arylating quinone derivatives of PAH and thiol and amine nucleophiles (Briggs, M.K., Desavis, E.D., Mazzer, P.A., and Hatcher, P.G., unpublished observations).…”