Document Detail

Sex differences in the metabolism of (+)- and (-)-limonene enantiomers to carveol and perillyl alcohol derivatives by cytochrome p450 enzymes in rat liver microsomes.
MedLine Citation:
PMID:  11800592     Owner:  NLM     Status:  MEDLINE    
(+)-Limonene is reported to cause nephropathy in male rats, but not in female rats and other species of animals including mice, rabbits, guinea pigs, and dogs. Male rats contain high levels of alpha2u-globulin in kidneys, and it has been shown that limonene and/or its metabolites are able to bind noncovalently to alpha2u-globulin, resulting in an accumulation of protein droplets in the renal tubules. In this study, we investigated whether (+)- and (-)-limonene enantiomers are differentially metabolized by liver microsomes of male and female rats. (+)- and (-)-limonene enantiomers were found to be oxidized to their respective trans-carveol (6-hydroxylation) and perillyl alcohol (7-hydroxylation) derivatives in greater amounts by liver microsomes of male rats than those of female rats. The limonene hydroxylation activities were not detected in liver microsomes of rat fetuses and were increased developmentally after birth, only in male rats. Treatment of male rats with phenobarbital significantly increased liver microsomal 6-hydroxylation activities with both enantiomers whereas beta-naphthoflavone, isosafrole, and pregnenolone 16alpha-carbonitrile did not cause such effects. Anti-P450 2C9 which cross-reacts with rat P450 2C11 inhibited limonene hydroxylations catalyzed by liver microsomes of untreated male rats, and it was also found that anti-P450 2B1 suppressed the activities catalyzed by liver microsomes of phenobarbital-treated rats. Possible roles of P450 2C11 and P450 2B1 in the limonene hydroxylation activities were supported by the experiments with purified rat liver P450s in reconstitution systems and with recombinant rat P450s in Trichoplusia ni. Our present results showing that there are sex-related differences in the oxidative metabolism of limonene enantiomers by liver microsomes may provide useful information on the basis of limonene-induced toxicities in different animal species.
Mitsuo Miyazawa; Masaki Shindo; Tsutomu Shimada
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  15     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2002 Jan 
Date Detail:
Created Date:  2002-01-21     Completed Date:  2002-03-22     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15-20     Citation Subset:  IM    
Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, Kowakae, Higashiosaka, Osaka 577-8502, Japan.
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MeSH Terms
Cytochrome P-450 Enzyme System / biosynthesis,  metabolism*
Enzyme Induction
Gas Chromatography-Mass Spectrometry
Microsomes, Liver / drug effects,  enzymology
Rats, Sprague-Dawley
Recombinant Proteins
Sex Factors
Terpenes / metabolism*
Reg. No./Substance:
0/Cyclohexenes; 0/Isoenzymes; 0/Monoterpenes; 0/Recombinant Proteins; 0/Terpenes; 138-86-3/limonene; 536-59-4/perilla alcohol; 9035-51-2/Cytochrome P-450 Enzyme System; 99-48-9/carveol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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