위장계 선분비 기능에 대한 vitamin A 유도체의 영향

Abstract

[영문]

[한글]

Vitamin A는 성장, 시력 및 생식기능에 관여하는 필수적 영양소이며 특히 상피세포의

각질화에 중요한 역할을 하여 부족시에는 모든 상피세포를 편평상피세포화 시키고 과다시

에는 절막화생을 일으켜 선분비 기능에 이상을 초래할 수 있다. 근연물질인 retinoic aci

d는vitamin A와 달리 시력과 생식에는 별 영향이 얼고 주로 성장에 관여하여 상피세포 및

골형성세포의 분화에 유효하다. 최근에는 retinoic acid 유도체로 retinoid (Ro 10-9359

)가 합성되어 retinoic acid 보다 독성은 적으면서 효과는 별 손색이 없다고 보고되어 있

다.

Vitamin A 및 유도제는 주로 간장에 저장되고 담즙으로 배설되는데 과다 시에는 lysoso

me 막에 영향을 주어 간세포 손상을 가져오며 다른 조직에서도 같은 결과를 초래할 수 있

다고 한다. 실험적으로 흰 쥐에 vitamins 및 retinoic acid를 투여하여 간세포에 지방변

성, Kupffer세포의 증식, 간세포의 핵증대, 염증세포의 침윤 및 부분적 괴사 유발을 관찰

보고한 바도 있다.

이상의 보고들을 참작할 때 vitamin A 및 유도체 투여로 간장, 처장, 위장 등, 위장계

선분비기능에 독성을 초래할 것으로 예견되고 또한 임상적으로 장기간 투여해야 유효하므

로 그 독성을 고려하지 않을 수 없다. 그러나 이들 약물이 위장계 선분비기능에 대한 보

고는 태무하므로 본 실험에 착수하였다.

이 실험에서 흰쥐에 vitamin A, retinoic acid 및 retinoid (Ro 10-9359)를 경구투여하

고 단회 투여군과 반복 투여군으로 나누어 위장계 선분비 기능변동을 검색하였다. 반복

투여군에서는 격일로 4회 투여 후 2주간 회복과정과 간장, 취장 및 위장의 병리조직학적

변화를 관찰하였다. 그 결과는 다음과 같다.

1. Retinoic acid와 retinoid 투여군에서 현저한 체중감소를 나타냈고 vitamin A 투여

군에서는 별다른 변동이 없었다. 또한 전 실험 기간 중 유독 retinoic acid 투여군에서

높은 치사율을 나타냈다.

2. Vitamin A및 유도체의 단회 투여실험에 있어서 담취액 분비량은 retinoic acid와vit

amin A 투여로 의의있는 증가를 나타냈고 cholate분비는 retinoic acid와 retinoid군에서

억제되었다.

3. 반복투여 실험에 있어서는 vitamin A 및 유도체의 4회 반복 투여로 심한 담취액 분

비기능의 억제가 나타났으며 전반적으로 투여완료 후 1주 내지 2주에는 취 및 담즙 분비

기능의 회복경향을 보였고 retinoid군에서 특히 빨랐다.

4. 혈청 alkaline phosphatase 활성은 단회 대량 투여실험에서 retinoid군에서만 의의

있게 상승하였으나 반복 투여 실험군에서는 별다른 변동을 초래하지 않았다.

5. Vitamin A 및 유도체 투여로 위산분비 항진을 나타냈고 특히 refinoid와 retinoic a

cid군에서 총산도의 현저한 증가를 초래하였다.

6. Retinoic acid 및 retinoid 반복 투여군에서 간세포의 지방변성 및 부분적 괴사가

초래되었고 vitamin A 및 retinoic acid군에서 위점막의 parietal cell층이 현저하게 증

가되었으나 취장의 형태학적 변화는 관찰할 수 없었다.

이상의 실힘성적으로 vitamin A 및 유도체는 위장계 선분비기능 특히 담즙산 (cholate)

분비기능의 변동을 나타내나 retinoic acid는 전반적으로 심한 선분비기능 장애를 보이

고 또한 높은 치사율을 나타내므로 대량 투여시에 각별한 유의를 요한다고 생각된다.

The Effect of Vitamin A Derivatives on Exocrine Functions of Digestive Glands in

Rats

Jung Bock Lee

Department of Medical Science The Gradurate School, Yonsei University

(Directed by Professor Sa Suk Hong and Professor Sungnack Lee)

From a great number of observations it is now recognized that vitamin A is

essential for the support of growth, vision and reproduction. Epithelial tissues in

particular appear to be regulated by this vitamin. Its absence causes squamous

metaplasia of epithelia in the respiratory tract, salivary gland atrophy, and

keratinization of pancreatic ducts and of bladder epithelium. In 나in, produced

hyperkeratinisation results in epidermal atrophy. Its excess, on the other hand,

causes mucous metaplasia in the epithelial tissues. It is of great interest that

the acid form (vitamin A acid: retinoic acid) will not satisfy the visual function

of vitamin A nor will it in moat cases satisfy the reproductive function of this

vitamin. However, it is mainly invoved in stimulating differentiation of epithelial

tissue. In recent years retinoic acid analogs (retinoids) have been synthesized and

shown to be more potent and fess toxic. Among a large series of retinoids the

aromatic analog (Ro 10-9359) proved to be particularly active preparation. The

liver is the main site of storage and excretion of vitamin A and its derivatives,

which produce tissue injury to the liver and other organs as a result of release of

the lysosomal enzymes in excess. It has been noted chat fatty vacuoles within

hepatozytes and Kupffer cells, increased number of Kupffer cells, enlarged nucleus

of hepatocyte, infiltration of inflammatory cells, and focal necrosis appeared in

the liver of vitamin A- as well as retinoic acid-treated rats. Beside these

changes, high doses of vitamin A or its derivatives may cause a change in secretory

functions by regulation of glandular epithelia of various organs such as liver,

pancreas or stomach. Since these drugs are therapeutically effective for skin

diseases only at long-term administration of large dories, their toxicities are an

important clinical consideration.

In the present work, we describe our findings that illustrate the effect of

vitamin A or its derivatives on the exocrine functions as well as on the histologic

changes of the main digestive glands, i.e. liver, pancreas and stomach of the rat.

Vitamin A, retinoic acid or retinoid(Ro 10-9359) was administered to the rats in a

large single dose or repeated doses. In the group receiving repeated

administrations the rats were treated with the drugs four times every other day and

then the course of recovery was observed during the following two weeks. The

results were summarized as follows :

1. The growth rates of the rats were markedly inhibited by retinoic acid, while

they were not significantly altered by vitamin A. The death rate was significantly

higher in retinoic acid-treated rats than in other groups.

2. In the group treated with single administration of vitamin A or its

derivatives, the volume of pancreaticobiliary secretion significantly increased in

retiroic acid- and vitamin A-treated animals, however, the concentration of cholate

was diminished in the retinoic acid and retinoic groups.

3. Pancreaticobiliary secretion was markedly inhibited by repeated

administrations of Vitamiin A or its derivatives. was a whole, it was shown that

the exocrine function recovered during the following two weeks after the completion

of treatment. Recovery following retinoid treatment was rapid.

4. Whereas the activity of serum alkaline phosphatase wart not affected by

repeated administrations of vitamin A or its derivatives, there was an increase in

the activity in theretinoid. treated rats with a large single administration.

5. The acid content of gastric juice increased in the rats treated with vitamin A

or its derivatives. The total acid of gastric juice increased particularly in the

rats treated wish retinoid or retinoic acid.

6. In the group receiving repeated administrations of vitamin A or its

derivatives, retinoic acid and retinoid caused a fatty change and a focal necrosis

of hepatocytes. The parietal cell mass significantly thickened in the gastric

mucosa of rats treated with vitamin A or retinoic acid, however, there was no

morphological change in the pancreas.

These data indicate that an excessive feeding of vitamin A or its derivatives,

particularly retinoic acid, reaults in a considerable toxicity and a change of

exocrine functions of the main digestive glands in the rats.