US EPA

32756 

Journal Article 

Genetic differences in cataract and other ocular abnormalities induced by paracetamol and naphthalene 

Shichi, H; Tanaka, M; Jensen, NM; Nebert, DW 

1980 

1 

Pharmacology
ISSN: 0031-7012
EISSN: 1423-0313 

20 

5 

229-241 

English 

7393992 

10.1159/000137369 

WOS:A1980JT53800001 

http://://WOS:A1980JT53800001
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Following induction of total body cytochrome Pr450 by 3-methylcholanthrene, there is a strong correlation between the Ahballele and cataract formation caused by large doses of intraperitoneal acetaminophen (1,000 mg/kg body weight) among 4 inbred mouse strains genetically ‘responsive’ at the Ah locus, 5 inbred strains genetically ‘nonresponsive’, and progeny of the (C57BL/6N) (DBA/2N)F1 x DBA/2N backcross. Two to five times more acetaminophen metabolites reach the lens and become covalently bound in 3-methylcholanfhrene-pretreated C57BL/6N than DBA/2N – in spite of no apparent depletion of reduced glutathione levels in the lens of either strain. It is therefore suggested that the mechanism of ocular toxicity without glutathione depletion may differ from that of hepatic necrosis, which occurs only when glutathione is depleted. Oral phenobarbital pretreatment completely prevents lenticular opacities in C57BL/6N with or without 3-methylcholanthrene pretreatment. Daily oral doses of acetaminophen or naphthalene (60–120 mg/kg/day) cause cataract formation in C57BL/6N concomitantly treated with 3-methylcholanthrene or β-naphthoflavone; no DBA/2N mice develop cataracts under these regimens. Some of these cataracts persisted in otherwise healthy C57BL/6N until they were killed for examination 6 or 7 months later. Histological signs of chronic toxicity were seen in the anterior lens cortex, charoid, ciliary body, and iris. These data illustrate the delicate balance between genetic and environmental factors causing ocular toxicity. Because drug-induced cataracts look clinically very similar to senile cataracts, these results may be important to patients receiving either a single large overdose of acetaminophen or high doses over a long period of time. 

Naphthalenes; Acetaminophen; 362O9ITL9D; Cytochrome P-450 Enzyme System; 9035-51-2; Glutathione; GAN16C9B8O; Phenobarbital; YQE403BP4D; Index Medicus; Glutathione -- metabolism; Species Specificity; Administration, Oral; Injections, Intraperitoneal; Lens, Crystalline -- metabolism; Enzyme Induction; Eye -- drug effects; Mice, Inbred Strains; Eye -- pathology; Liver -- metabolism; Animals; Cytochrome P-450 Enzyme System -- biosynthesis; Liver -- drug effects; Phenobarbital -- pharmacology; Cytochrome P-450 Enzyme System -- metabolism; Acetaminophen -- toxicity; Cataract -- genetics; Eye Diseases -- chemically induced; Acetaminophen -- metabolism; Naphthalenes -- toxicity; Cataract -- chemically induced; Naphthalenes -- metabolism