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Monocrotaline (MCT) is bioactivated in liver cytochrome P-450s to MCT pyrrole (MCTP), which primarily injures the lung endothelium to result in the development of pulmonary hypertension (PH) in rats. However, whether there is a relation between the degree of PH and the activity of liver cytochrome P-450 to convert MCT to MCTP remains unclear. To examine the relation between these physiological and biochemical changes, we first measured the severity of MCT-induced (20 mg/kg) PH in male, female, castrated male, and phenobarbital (PB, liver P-450s inducer)-pretreated male rats. The degree of right ventricular hypertrophy was more severe in PB-pretreated male than in control male rats. It was also more severe in male than in either female or castrated male rats, suggesting that sex-specific P-450s could be involved in the metabolic pathways of MCT in the liver. Further to explore which of the isozymes (2A2, 2C11, and 3A) of P-450s in the liver is responsible for the bioactivation of MCT, we measured the rate of MCTP production in hepatic microsomes by a modified Mattock's method. Treatment of male rats with PB and pregnenolone 16alpha-carbonitrile (PCN), which is the specific inducer of P-450 3A, increased the rate of MCTP production, suggesting that P-450 3A may contribute to the conversion to pyrrole. Therefore we measured the amount of P-450 3A protein by immunoblotting and attempted to inhibit MCT metabolism by using antibodies to P-450 3A. P-450 3A was significantly induced by PCN (6.5-fold) and PB (4.6-fold) treatment and reduced by castration (0.38-fold). The amount of P-450 3A was closely correlated with the production of MCTP, and the conversion of MCT to MCTP was strongly inhibited by antibodies against P-450 3A. These results indicated that P-450 3A was predominantly responsible for the metabolism of MCT to MCTP in rat liver and suggested a tight linkage between the degree of PH and the activity of liver P-450 3A.
Y Kasahara, and
K Kiyatake, and
K Tatsumi, and
K Sugito, and
I Kakusaka, and
S Yamagata, and
S Ohmori, and
M Kitada, and
T Kuriyama
January 1989,
Drug metabolism and disposition: the biological fate of chemicals,
Y Kasahara, and
K Kiyatake, and
K Tatsumi, and
K Sugito, and
I Kakusaka, and
S Yamagata, and
S Ohmori, and
M Kitada, and
T Kuriyama
October 1992,
Liver,
Y Kasahara, and
K Kiyatake, and
K Tatsumi, and
K Sugito, and
I Kakusaka, and
S Yamagata, and
S Ohmori, and
M Kitada, and
T Kuriyama
January 1983,
Pharmacology, biochemistry, and behavior,
Y Kasahara, and
K Kiyatake, and
K Tatsumi, and
K Sugito, and
I Kakusaka, and
S Yamagata, and
S Ohmori, and
M Kitada, and
T Kuriyama
July 1995,
The Biochemical journal,
Y Kasahara, and
K Kiyatake, and
K Tatsumi, and
K Sugito, and
I Kakusaka, and
S Yamagata, and
S Ohmori, and
M Kitada, and
T Kuriyama
January 1993,
Drug metabolism and disposition: the biological fate of chemicals,
Y Kasahara, and
K Kiyatake, and
K Tatsumi, and
K Sugito, and
I Kakusaka, and
S Yamagata, and
S Ohmori, and
M Kitada, and
T Kuriyama
May 1986,
Archives of biochemistry and biophysics,
Y Kasahara, and
K Kiyatake, and
K Tatsumi, and
K Sugito, and
I Kakusaka, and
S Yamagata, and
S Ohmori, and
M Kitada, and
T Kuriyama
September 1987,
Biochemical pharmacology,
Y Kasahara, and
K Kiyatake, and
K Tatsumi, and
K Sugito, and
I Kakusaka, and
S Yamagata, and
S Ohmori, and
M Kitada, and
T Kuriyama
July 1992,
The Journal of pharmacology and experimental therapeutics,
Y Kasahara, and
K Kiyatake, and
K Tatsumi, and
K Sugito, and
I Kakusaka, and
S Yamagata, and
S Ohmori, and
M Kitada, and
T Kuriyama
November 1997,
European journal of biochemistry,
Y Kasahara, and
K Kiyatake, and
K Tatsumi, and
K Sugito, and
I Kakusaka, and
S Yamagata, and
S Ohmori, and
M Kitada, and
T Kuriyama
May 1982,
Biochemistry,
