Sex differences in hexachlorobutadiene biotransformation and nephrotoxicity

Area of Science:

• Toxicology
• Environmental Chemistry
• Biochemistry

Background:

• Hexachlorobutadiene (HCBD) is a nephrotoxic industrial chemical.
• Renal toxicity is linked to bioactivation via glutathione S-conjugate formation.
• Previous studies suggest N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (N-ac-PCBC) accumulation in kidneys.

Purpose of the Study:

• To investigate the distribution and biotransformation of [14C]HCBD in male and female Wistar rats.
• To identify novel bioactivation pathways and elucidate sex differences in HCBD nephrotoxicity.

Main Methods:

• Administration of [14C]HCBD (200 mg/kg) via gavage to male and female rats.
• Analysis of radioactivity excretion in feces and urine.
• Identification of metabolites using techniques like HPLC and mass spectrometry.
• In vitro studies using rat renal tubular cells and liver microsomes.

Main Results:

• No significant sex differences in HCBD disposition or excretion rates were observed.
• Male rats excreted N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide (N-ac-PCBC sulfoxide), a novel metabolite, not significantly found in females.
• N-ac-PCBC sulfoxide induced greater cell death in renal tubular cells compared to N-ac-PCBC.
• Male rats showed increased renal necrosis and mild liver changes compared to females.
• Liver microsomes from male rats catalyzed N-ac-PCBC sulfoxide formation.

Conclusions:

• A new beta-lyase-independent bioactivation pathway involving N-ac-PCBC sulfoxide formation exists in male rats.
• This mercapturic acid sulfoxide pathway may explain the observed sex differences in hexachlorobutadiene-induced nephrotoxicity.
• Further research into this pathway could inform risk assessment and mitigation strategies for HCBD exposure.