Sex difference in susceptibility to acetaminophen hepatotoxicity

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*Sex* *difference* in *susceptibility* to *acetaminophen*

*hepatotoxicity* is *reversed* by *buthionine* *sulfoximine*.

<http://www.ncbi.nlm.nih.gov/pubmed/21672600>

Masubuchi Y, Nakayama J, Watanabe Y.

Toxicology. 2011 Jun 6.

Gender is a factor that influences susceptibility of individuals to

drug-induced liver injury in experimental animals and humans. In this

study, we investigated the mechanisms underlying resistance of female

mice to acetaminophen (APAP)-induced hepatotoxicity. Overnight-fasted

male and female CD-1 mice were administered APAP intraperitoneally. A

minor increase in serum alanine aminotransferase levels was observed in

female mice after APAP administration at a dose that causes severe

hepatotoxicity in males. Hepatic glutathione (GSH) depleted rapidly in

the both genders prior to development of hepatotoxicity, whereas its

recovery was more rapid in female than in male mice. This was consistent

with higher induction of hepatic glutamate-cysteine ligase (GCL) in

females. Pretreatment of mice with L-buthionine sulfoximine (BSO), an

inhibitor of GCL, exaggerated APAP hepatotoxicity only in female mice,

resulting in much higher hepatotoxicity in female than in male mice. In

addition, hepatic GSH was markedly depleted in BSO-pretreated female

mice compared with male mice, which supports severe hepatotoxicity in

BSO-pretreated females. APAP treatment highly induced multidrug

resistance-associated protein 4 (Mrp4) only in female mice. The

resulting high Mrp4 expression could thus contribute to decreased

hepatic GSH levels via sinusoidal efflux when GCL is inhibited. In

conclusion, resistance to APAP hepatotoxicity in female mice and its

reversal by pretreatment with BSO could be attributed to sex differences

in disposition of hepatic GSH, which may generally determine

susceptibility to drug-induced liver injury.

*Sex*- and age-dependent *acetaminophen* hepato- and nephrotoxicity in

Sprague-Dawley rats: role of tissue accumulation, nonprotein sulfhydryl

depletion, and covalent binding.

<http://www.ncbi.nlm.nih.gov/pubmed/8812206>

Tarloff JB, Khairallah EA, Cohen SD, Goldstein RS.

Fundam Appl Toxicol. 1996 Mar;30(1):13-22.

*Acetaminophen* metabolism does not contribute to gender *difference* in

its *hepatotoxicity* in mouse. <http://www.ncbi.nlm.nih.gov/pubmed/16611625>

Dai G, He L, Chou N, Wan YJ.

Toxicol Sci. 2006 Jul;92(1):33-41.